Pyrazole derivatives-p38 map kinase inhibitors

ABSTRACT

The present invention relates to certain pyrazole derivatives of Formula (I):                    
     that are p-38 MAP kinase inhibitors, pharmaceutical compositions containing them, methods for their use, and methods for preparing these compounds.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit under 35 U.S.C. 119(e) of U.S.Provisional Application Ser. No. 60/084,250, filed May 5, 1998, Ser. No.60/122,410, filed Mar. 2, 1999 and Ser. No. 60/130,369, filed Apr. 21,1999, hereby incorporated by reference in their entirety.

FIELD OF THE INVENTION

This invention relates to certain pyrazole derivatives that inhibit p38MAP kinase, pharmaceutical compositions containing them, methods fortheir use, and methods for preparing these compounds.

BACKGROUND INFORMATION AND RELATED DISCLOSURES

TNF and IL-1 have been shown to be central players in the pathologicalprocesses underlying many chronic inflammatory and autoimmune diseases.IL-1 is implicated in mediating or exacerbating diseases such asrheumatoid arthritis ((see., Arend, W. P. Arthritis & Rheumatism 38(2):151-160, (1995)), osteoarthritis, bone resorption, toxic shock syndrome,tuberculosis, atherosclerosis, diabetes, Hodgkin's disease (see.,Benharroch, D.; et. al. Euro. Cytokine Network 7(1): 51-57) andAlzheimer's disease. Excessive or unregulated TNF production has beenimplicated in mediating or exacerbating diseases such as rheumatoidarthritis ((see., Maini, R. N.; et. al. APMIS. 105(4): 257-263, (1997);Feldmann, M., J. of the Royal College of Physicians of London 30(6):560-570, (1996); Lorenz, H. M.; et. al. J. of Immunology 156(4):1646-1653, (1996)) osteoarthritis, spondylitis, sepsis, septic shock((see., Abraham, E.; et. al. JAMA. 277(19):1531-1538, (1997), adultrespiratory distress syndrome, asthma ((see., Shah, A.; et. al. Clin. &Exp. Allergy 1038-1044, (1995) and Lassalle, P., et. al. Clin. & Exp.Immunol. 94(1): 105-110, (1993)), bone resorption diseases, fever((see., Cooper, A. L., et. al. Am. J. of Physiology 267(6 Pt. 2):1431-1436)), encephalomyelitis, demyelination ((see., Klindert, W. E.;et al. J. of Neuroimmunol. 72(2): 163-168, (1997)) and periodontaldiseases.

Clinical trials with IL-1 and TNF receptor antagonists have shown thatblocking the ability of these cytokines to signal through theirreceptors leads to significant improvement, in humans, in inflammatorydiseases. Therefore, modulation of these inflammatory cytokines isconsidered one of the most effective strategies to block chronicinflammation and have positive therapeutic outcomes. It has also beenshown that p38 MAP kinase plays an important role in the translationalcontrol of TNF and IL-1 and is also involved in the biochemicalsignaling of these molecules ((see., Lee, J. C., et al. Nature. 372(6508): 73946, (1994)). Compounds that bind to p38 MAP are effective ininhibiting bone resorption, inflammation, and other immune andinflammation-based pathologies. The characterization of the p38 MAPkinase and its central role in the biosynthesis of TNF and IL-1 havemade this kinase an attractive target for the treatment of diseasesmediated by these cytokines.

It would therefore be desirable to provide p38 MAP kinase inhibitors andthereby provide a means of combating diseases mediated bypro-inflammatory cytokines such as TNF and IL-1. This invention fulfillsthis and related needs.

SUMMARY OF THE INVENTION

In a first aspect, this invention provides compounds selected from thegroup of compounds represented by Formula (I):

wherein:

R¹ is hydrogen or acyl;

R² is hydrogen or alkyl;

A is an aryl or heteroaryl ring;

B is an aryl or heteroaryl ring;

R³ is selected from the group consisting of:

(a) amino, alkylamino or dialkylamino:

(b) acylamino;

(c) optionally substituted heterocyclyl;

(d) optionally substituted aryl or heteroaryl;

(e) heteroalkyl;

(f) heteroalkenyl;

(g) heteroalkynyl;

(h) heteroalkoxy;

(i) heteroalkylamino;

(j) optionally substituted heterocyclylalkyl;

(k) optionally substituted heterocyclylalkenyl;

(l) optionally substituted heterocyclylalkynyl;

(m) optionally substituted heterocyclylalkoxy, cyclyloxy orheterocyclyloxy;

(n) optionally substituted heterocyclylalkylamino;

(o) optionally substituted heterocyclylalkylcarbonyl;

(p) heteroalkylcarbonyl;

(q) —NHSO₂R⁶ where R⁶ is alkyl, heteroalkyl or optionally substitutedheterocyclylalkyl;

(r) —NHSO₂NR⁷R⁸ where R⁷ and R⁸ are, independently of each other,hydrogen, alkyl or heteroalkyl;

(s) —Y—(alkylene)—R⁹ where:

Y is a single bond, —O—, —NH— or —S(O)_(n)— (where n is an integer from0 to 2); and

R⁹ is cyano, optionally substituted heteroaryl, —COOH, —COR¹⁰, —COOR¹¹,—CONR¹²R¹³, —SO₂R¹⁴, —SO₂NR¹⁵R¹⁶, —NHSO₂R¹⁷ or —NHSO₂NR¹⁸R¹⁹, where R¹⁰is alkyl or optionally substituted heterocycle, R¹¹ is alkyl, and R¹²,R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸ and R¹⁹ are, independently of each other,hydrogen, alkyl or heteroalkyl;

(t) —C(═NR²⁰)(NR²¹R²²) where R²⁰, R²¹ and R²² independently representhydrogen, alkyl or hydroxy, or R²⁰ and R²¹ together are —(CH₂)_(n)—where n is 2 or 3 and R²² is hydrogen or alkyl;

(u) —NHC(X)NR²³R²⁴ where X is —O— or —S—, and R²³ and R²⁴ are,independently of each other, hydrogen, alkyl or heteroalkyl;

(v) —CONR²⁵R²⁶ where R²⁵ and R²⁶ independently represent hydrogen,alkyl, heteroalkyl or optionally substituted heterocyclylalkyl, or R²⁵and R²⁶ together with the nitrogen to which they are attached form anoptionally substituted heterocyclyl ring;

(w) —S(O)_(n)R²⁷ where n is an integer from 0 to 2, and R²⁷ is alkyl,heteroalkyl, optionally substituted heterocyclylalkyl or —NR²⁸R²⁹ whereR²⁸ and R²⁹ are, independently of each other, hydrogen, alkyl orheteroalkyl;

(x) cycloalkylalkyl, cycloalkylalkynyl and cycloalkylalkynyl, alloptionally substituted with alkyl, halo, hydroxy or amino;

(y) arylaminoalkylene or heteroarylaminoalkylene;

(z) Z-alkylene-NR³⁰R³¹ or Z-alkylene-OR³² where Z is —NH—, —N(alkyl)— or—O—, and R³⁰, R³¹ and R³² are independently of each other, hydrogen,alkyl or heteroalkyl;

(aa) —OC(O)-alkylene-CO₂H or —OC(O)—NR′R″ (where R′ and R″ areindependently hydrogen or alkyl); and

(bb) heteroarylalkenylene or heteroarylalkynylene;

R⁴ is selected from the group consisting of.

(a) hydrogen;

(b) halo;

(c) alkyl;

(d) alkoxy; and

(e) hydroxy;

R⁵ is selected from the group consisting of:

(a) hydrogen;

(b) halo;

(c) alkyl;

(d) haloalkyl;

(e) thioalkyl;

(f) hydroxy;

(g) amino;

(h) alkylamino;

(i) dialkylarnino;

(j) heteroalkyl;

(k) optionally substituted heterocycle;

(l) optionally substituted heterocycylalkyl;

(m) optionally substituted heterocyclylalkoxy;

(n) alkylsulfonyl;

(o) aminosulfonyl, mono-alkylaminosulfonyl or dialkylaminosulfonyl;

(p) heteroalkoxy; and

(q) carboxy;

R⁶ is selected from a group consisting of:

(a) hydrogen;

(b) halo;

(c) alkyl; and

(d) alkoxy;

prodrugs, individual isomers, mixtures of isomers and pharmaceuticallyacceptable salts thereof.

In a second aspect, this invention provides pharmaceutical compositionscontaining a therapeutically effective amount of a compound of Formula(I) or its pharmaceutically acceptable salt and a pharmaceuticallyacceptable excipient.

In a third aspect, this invention provides a method of treatment of adisease in a mammal treatable by administration of a p38 MAP kinaseinhibitor, comprising administration of a therapeutically effectiveamount of a compound of Formula (I) or its pharmaceutically acceptablesalt.

In a fourth aspect, this invention provides processes for preparingcompounds of Formula (I).

DETAILED DESCRIPTION OF THE INVENTION Definitions

Unless otherwise stated, the following terms used in the specificationand claims have the meanings given below:

“Alkyl” means a linear saturated monovalent hydrocarbon radical of oneto six carbon atoms or a branched saturated monovalent hydrocarbonradical of three to six carbon atoms, e.g., methyl, ethyl, propyl,2-propyl, pentyl, and the like.

“Alkylene” means a linear saturated divalent hydrocarbon radical of oneto six carbon atoms or a branched saturated divalent hydrocarbon radicalof three to six carbon atoms, e.g., methylene, ethylene, propylene,2-methylpropylene, pentylene, and the like.

“Alkenyl” means a linear monovalent hydrocarbon radical of two to sixcarbon atoms or a branched monovalent hydrocarbon radical of three tosix carbon atoms, containing at least one double bond, e.g., ethenyl,propenyl, and the like.

“Alkenylene” means a linear divalent hydrocarbon radical of two to sixcarbon atoms or a branched divalent hydrocarbon radical of three to sixcarbon atoms, containing at least one double bond, e.g., ethenylene,propenylene, and the like.

“Alkynyl” means a linear monovalent hydrocarbon radical of two to sixcarbon atoms or a branched divalent hydrocarbon radical of three to sixcarbon atoms, containing at least one triple bond, e.g., ethynyl,propynyl, and the like.

“Alkynylene” means a linear divalent hydrocarbon radical of two to sixcarbon atoms or a branched monovalent hydrocarbon radical of three tosix carbon atoms, containing at least one triple bond, e.g., ethynylene,propynylene, and the like.

“Alkoxy” means a radical —OR where R is alkyl as defined above, e.g.,methoxy, ethoxy, propoxy, 2-propoxy, the like.

“Acyl” means a radical —C(O)R where R is alkyl or haloalkyl e.g.,acetyl, trifluoroacetyl, and the like.

“Acylamino” means a radical —NRC(O)R′ where R is hydrogen or alkyl, andR′ is alkyl, heteroalkyl or optionally substituted heterocyclylalkyl,e.g., acetylamino, 2-amino-2-methylpropionamide, and the like.

“Halo” means fluoro, chloro, bromo, or iodo, preferably fluoro andchloro.

“Haloalkyl” means alkyl substituted with one or more same or differenthalo atoms, e.g., —CH₂Cl, —CF₃, —CH₂CF₃, —CH₂CCl₃, and the like.

“Aryl” means a monovalent monocyclic or bicyclic aromatic hydrocarbonradical of 6 to 10 ring atoms e.g., phenyl, 1-naphthyl, 2-naphthyl, andthe like. The aryl ring may optionally be fused to a 5-, 6- or 7-membered monocyclic saturated ring optionally containing 1 or 2heteroatoms independently selected from oxygen, nitrogen or sulfur, theremaining ring atoms being C where one or two C atoms are optionallyreplaced by a carbonyl group. Representative aryl radicals with fusedrings include, but are not limited to, 2,3-dihydrobenzo[1,4]dioxan,chroman, isochroman, 2,3-dihydrobenzofuran, 1,3-dihydroisobenzofuran,benzo[1,3]dioxole, 1,2,3,4-tetrahydroisoquinoline,1,2,3,4-tetrahydroquinoline, 2,3-dihydro-1H-indole,2,3-dihydro-1H-isoindole, benzimidazol-2-one, 3H-benzoxazol-2-one, andthe like.

“Heteroaryl” means a monovalent monocyclic or bicyclic aromatic radicalof 5 to 10 ring atoms containing one, two, or three ring heteroatomsselected from N, O, or S, the remaining ring atoms being C. The termalso includes those radicals where a heteroatom within the ring has beenoxidized or quatemized, such as, for example, to form an N-oxide or aquaternary salt. Representative examples include, but are not limitedto, thienyl, benzothienyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,quinolinyl, quinoxalinyl, imidazolyl, furanyl, benzofuranyl, thiazolyl,isoxazolyl, benzisoxazolyl, benzimidazolyl, triazolyl, pyrazolyl,pyrrolyl, indolyl, 2-pyridonyl, 4-pyridonyl, N-alkyl-2-pyridonyl,pyrazinonyl, pyridazinonyl, pyrimidinonyl, oxazolonyl, and theircorresponding N-oxides, (e.g. pyridyl N-oxide, quinolinyl N-oxide),their quaternary salts and the like.

“Heterocycle” or “heterocyclyl” means a cyclic nonaromatic radical of 3to 8 ring atoms in which one or two ring atoms are heteroatoms selectedfrom N, O, or S(O)_(n) (where n is an integer from 0 to 2), theremaining ring atoms being C where one or two C atoms are optionallyreplaced by a carbonyl group. The term also includes those radicalswhere a ring nitrogen atom has been oxidized or quaternized, such as,for example, to form an N-oxide or a quaternary salt. Representativeexamples include, but are not limited to, tetrahydropyranyl,tetrahydrofuranyl, tetrahydrothiophenyl, piperidino, morpholino,piperazino, pyrrolidino, oxiranyl, dioxane, 1,3-dioxolanyl,2,2-dimethyl-1,3-dioxalanyl, sulfolanyl, 2-oxazolidonyl,2-imidazolidonyl, S,S-dioxo-thiomorpholino, and the like.

“Heterocycloamnino” means a saturated monovalent cyclic group of 4 to 8ring atoms, wherein at least one ring atom is N and optionally containsone additional ring atom selected from N or O, the remaining ring atomsbeing C. The term includes groups such as pyrrolidino, piperidino,morpholino, piperazino and the like.

“Optionally substituted aryl, heteroaryl or heterocyclyl” means an aryl,heteroaryl or heterocyclyl ring as defined above, which is optionallysubstituted independently with one or two substituents selected fromalkyl, phenyl, benzyl, haloalkyl, heteroalkyl, halo, cyano, acyl, —OR(where R is hydrogen or alkyl), —NRR′ (where R and R′ are independentlyselected from hydrogen, alkyl or acyl), —NHCOR (where R is alkyl),—NRS(O)_(n)R′ (where R is hydrogen or alkyl, n is an nteger from 0 to 2and R′ is hydrogen, alkyl or heteroalkyl), —NRS(O)_(n)NR′R″ (where R ishydrogen or alkyl, n is an integer from 0 to 2 and R′ and R″ areindependently hydrogen, alkyl or heteroalkyl), —S(O)_(n)R (where n is aninteger from 0 to 2 and R is hydrogen, alkyl or heteroalkyl),—S(O)_(n)NRR′ (where n is an integer from 0 to 2 and R and R′ areindependently hydrogen, alkyl or heteroalkyl), —COOR, —(alkylene)COOR(where R is hydrogen or alkyl), —CONR′R″ or —(alkylene)CONR′R″ (where R′and R″ are independently hydrogen or alkyl).

“Heteroalkyl” means an alkyl radical as defined above, carrying one, twoor three substituents selected from —NR^(a)R^(b), —OR^(c) wherein R^(a),R^(b) and R^(c) are independently of each other hydrogen, alkyl or acyl,or R^(a) and R^(b) together form heterocycloamino group. Representativeexamples include, but are not limited to, hydroxymethyl, acetoxymethyl,3-hydroxypropyl, 1,2-dihydroxyethyl, 2-methoxyethyl, 2-aminoethyl,2-dimethylaminoethyl, 2-acetylaminoethyl, 3-[pyrrolidin-1-yl]ethyl andthe like.

“Heteroalkenyl” means an alkenyl radical as defined above, carrying oneor two substituents selected from —NR^(a)R^(b), —OR^(c) or—S(O)_(n)R^(d) wherein R^(a), R^(b) and R^(c) are independently of eachother hydrogen or alkyl, and R^(d) is alkyl or —NRR′ (where R and R′ areindependently of each other hydrogen or alkyl. Representative examplesinclude, but are not limited to, 3-hydroxy-1-propenyl,3-aminoprop-1-enyl, 2-aminosulfonylethenyl, 2-methylsulfonylethenyl, andthe like.

“Heteroalkynyl” means an alkynyl radical as defined above, carrying oneor two substituents selected —NR^(a)R^(b), —OR^(c), —S(O)_(n)R^(d) or—S(O)_(n)NRR′ (where R and R′ are independently of each other hydrogenor alkyl) wherein R^(a), R^(b) and R^(c) are independently of each otherhydrogen or alkyl, and R^(d) is alkyl and n is an integer from zero totwo. Representative examples include, but are not limited to,3-hydroxy-1-propynyl, 3-dimethylaminoprop-1-ynyl and the like.

“Heteroalkoxy” means a radical —OR where R is heteroalkyl group asdefined above, e.g., 2-hydroxyethoxy, 3-hydroxypropoxy,2,3-dihydroxypropoxy, 2-(1,3-dihydroxy)propoxy, 2-aminoethoxy, and thelike.

“Heteroalkylamino” means a radical —NR^(a)R^(b) where R^(a) is hydrogenor alkyl, and R^(b) is a heteroalkyl group as defined above, e.g.,2-hydroxyethylamino, 3-dimethylaminopropylamino, and the like.

“Optionally substituted heterocyclylalkyl” means a radical —R^(a)R^(b)where R^(a) is an alkylene group, and R^(b) is an optionally substitutedheterocyclyl group as defined above e.g., 2-(morpholin-4-yl)ethyl,3-(piperidin-1-yl)-2-methylpropyl, and the like.

“Optionally substituted heterocyclylalkenyl” means a radical —R^(a)R^(b)where R^(a) is an alkenylene group and R^(b) is an optionallysubstituted heterocyclyl group as defined above e.g.,3-(morpholin-4-yl)prop-1-enyl, 3-(piperidin-1-yl)prop-1-enyl,3-(4-methylpiperazin-1-yl)prop-1-enyl, and the like.

“Optionally substituted heterocyclylalkynyl” means a radical —R^(a)R^(b)where R^(a) is an alkynyl group and R^(b) is an optionally substitutedheterocyclyl group as defined above e.g., 3-(morpholin-4-yl)prop-1-ynyl,3-(piperidin-1-yl)lprop-1-ynyl, and the like.

“Optionally substituted heterocyclylalkoxy” means a radical —OR where Ris an optionally substituted heterocyclylalkyl group as defined above,e.g., 2-(morpholin-4-yl)-ethoxy, 3-(piperazin-1-yl)propoxy,2-[2-oxopyrrolidin-1-yl]ethoxy, and the like.

“Optionally substituted heterocyclylalkylamino” means a radical—NR^(a)R^(b) where R^(a) is hydrogen or alkyl and R^(b) is an optionallysubstituted heterocyclylalkyl group as defined above, e.g.,2-(pyrrolidin-2-yl)ethylamino, 3-(piperidin-1-yl)propylamino, and thelike.

“Optionally substituted heteroaralkyloxy means a radical —O—R^(a) whereR^(a) is a heteroaralkyl radical e.g. 2-(pyridin-3-yl)ethoxy,2-[3(2H)-pyridazon-1-yl]ethoxy and the like.

“Optional” or “optionally” means that the subsequently described eventor circumstance may but need not occur, and that the descriptionincludes instances where the event or circumstance occurs and instancesin which it does not. For example, “aryl group optionally mono- or di-substituted with an alkyl group” means that the alkyl may but need notbe present, and the description includes situations where the aryl groupis mono- or disubstituted with an alkyl group and situations where theheterocyclo group is not substituted with the alkyl group.

“Amino protecting group” refers to those organic groups intended toprotect nitrogen atoms against undesirable reactions during syntheticprocedures e.g., benzyl, benzyloxycarbonyl (CBZ), tert-butoxycarbonyl(Boc), trifluoroacetyl, and the like.

The compounds of this invention may possess one or more asymmetriccenters; such compounds can therefore be produced as individual (R)- or(S)-stereoisomers or as mixtures thereof. Unless indicated otherwise,the description or naming of a particular compound in the specificationand claims is intended to include both individual enantiomers andmixtures, racemic or otherwise, thereof. The methods for thedetermination of stereochemistry and the separation of stereoisomers arewell-known in the art (see discussion in Chapter 4 of “Advanced OrganicChemistry”, 4th edition J. March, John Wiley and Sons, New York, 1992).

A “pharmaceutically acceptable excipient” means an excipient that isuseful in preparing a pharmaceutical composition that is generally safe,non-toxic and neither biologically nor otherwise undesirable, andincludes an excipient that is acceptable for veterinary use as well ashuman pharmaceutical use. “A pharmaceutically acceptable excipient” asused in the specification and claims includes both one and more than onesuch excipient.

A “pharmaceutically acceptable salt” of a compound means a salt that ispharmaceutically acceptable and that possesses the desiredpharmacological activity of the parent compound. Such salts include:

(1) acid addition salts, formed with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like; or formed with organic acids such asacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid,glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid,malic acid, maleic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelicacid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonicacid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-napthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,4,4′-methylenebis- (3-hydroxy-2-ene-1-carboxylic acid),3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynapthoicacid, salicylic acid, stearic acid, muconic acid, and the like; or

(2) salts formed when an acidic proton present in the parent compoundeither is replaced by a metal ion, e.g., an alkali metal ion, analkaline earth ion, or an aluminum ion; or coordinates with an organicbase such as ethanolamine, diethanolamine, triethanolamine,tromethamine, N-methylglucamine, and the like.

“Pro-drugs” means any compound which releases an active parent drugaccording to Formula (I) in vivo when such prodrug is administered to amammalian subject. Prodrugs of a compound of Formula (I) are prepared bymodifying functional groups present in the compound of Formula (I) insuch a way that the modifications may be cleaved in vivo to release theparent compound. Prodrugs include compounds of Formula (I) wherein ahydroxy, amino, or sulfhydryl group in compound (I) is bonded to anygroup that may be cleaved in vivo to regenerate the free hydroxyl,amino, or sulfhydryl grojup, respectively. Examples of prodrugs include,but are not limited to esters (e.g., acetate, formate, and benzoatederivatives), carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxyfunctional groups in compounds of Formula (I), and the like.

“Treating” or “treatment” of a disease includes:

(1) preventing the disease, i.e. causing the clinical symptoms of thedisease not to develop in a mammal that may be exposed to or predisposedto the disease but does not yet experience or display symptoms of thedisease,

(2) inhibiting the disease, i.e., arresting or reducing the developmentof the disease or its clinical symptoms, or

(3) relieving the disease, i.e., causing regression of the disease orits clinical symptoms.

A “therapeutically effective amount” means the amount of a compoundthat, when administered to a mammal for treating a disease, issufficient to effect such treatment for the disease. The“therapeutically effective amount” will vary depending on the compound,the disease and its severity and the age, weight, etc., of the mammal tobe treated.

NOMENCLATURE

The naming and numbering of the compounds of this invention isillustrated below.

The nomenclature used in this application is generally based on theIUPAC recommendations, e.g., a compound of formula (I):

where R¹, R², R⁴, R⁶ are hydrogen,

 is 4-(3-hydroxypropyl)phenyl and

 is 4-fluorophenyl is named5-amino-1-(4-fluorophenyl)-4-[4-(3-hydroxypropyl)-benzoyl]parazole.

where R¹, R², R⁴, R⁶ are hydrogen,

 is 3-[3-(morpholin-4-yl)prop-1-ynyl]-phenyl and

 is 4-fluorophenyl is named5-amino-1-(4-fluorophenyl)-4-[3-(3-morpholin-4-ylprop-1-ynyl)benzoyl]pyrazole.

CPD #

R⁵ R⁶ M. Pt. ° C. Mass Spec. (M⁺) 1 4-(3-hydroxypropyl)phenyl H H  148-152.5 2 4-[3-(morpholin-4-yl)prop-1-enyl]phenyl 4-F H 166.7-168.23 3-[3-(morpholin-4-yl)prop-1-ynyl]phenyl 4-F H 145.2-145.8 43-[3-(morpholin-4-yl)prop-1-enyl]phenyl 4-F H 161.6-162.8 54-[3-(morpholin-4-yl)propyl]phenyl 4-F.HCl H 408 63-[3-(morpholin-4-yl)propyl]phenyl 4-F.HCl H 211.9-212.6 73-(3-hydroxyprop-1-ynyl)phenyl 4-F H 219.2-219.6 83-[3-(4-methylpiperazin-1-yl)prop-1-ynyl]phenyl 4-F.2HCl H 270.8-271.1 93-[3-(piperidin-1-yl)prop-1-ynyl]phenyl 4-F.HCl H 205.3-207.4 103-(2-aminosulfonylethenyl)phenyl 4-F H 370 11 3-cyanomethyloxyphenyl 4-FH 12 3-[3-dimethylaminoprop-1-ynyl)]phenyl 4-F.HCl H 229.9-230   133-[2-(morpholin-4-yl)ethoxy]phenyl 4-F H 143-[2-(morpholin-4-yl)ethoxy]phenyl 4-F.HCl H 191.6-192.5 153-[2-(morpholin-4-yl)ethoxy]phenyl 2-F 4-F 428 163-(3-methylaminoprop-1-ynyl)phenyl 4-F H 210.6-210.8 173-(4-methylpiperazin-1-yl)phenyl 2-F.HCl H 142.5-151   183-(morpholin-4-ylmethylcarbonyl)phenyl 4-F.HCl H 408 193-(formamidoxime)phenyl 4-F H   227-231.8 20 3-(pyridin-3-yl)phenyl 4-FH 222.4-223.0 21 3-[3-(piperidin-1-yl)propoxy]phenyl 4-F H 422 223-[2-(piperidin-1-yl)ethoxy]phenyl 4-F H 408 233-[3-(morpholin-4-yl)propoxy]phenyl 4-F H 424 243-[3-(4-methylpiperazin-1-yl)propoxy]phenyl 4-F H 437 253-[3-(2-hydroxymethylpyrrolidin-1-yl)propoxy]-phenyl 4-F H 438 263-[3-(2-aminocarbonylpyrrolidin-1-yl)propoxy]-phenyl 4-F H 273-(3-cyanopropoxy)phenyl 4-F H 364 28 3-(3-diethylaminopropoxy)phenyl4-F H 410 29 2-[3-(4-methylpiperazin-1-yl)propoxy]phenyl 4-F H 437 303-[3-(4-methylpiperazin-1-yl)propyl]phenyl 4-F.2HCl H 254.5-254.9 313-[3-(4-methylpiperazin-1-yl)ethyl]phenyl 4-F.2HCl H 272.9-273.9 323-[3-(piperidin-1-yl)propyl]phenyl 4-F.HCl H 227.1-277.7 333-(4-benzylpiperidin-1-yl)phenyl 4-F H 156.2-160.9 343-(methylaminocarbonylmethyloxy)phenyl 4-F H 195.6-196.3 353-(morpholin-4-ylcarbonylmethyloxy)phenyl 4-F H 124.3-126.6 363-(piperidin-1-ylcarbonylmethyloxy)phenyl 4-F H 422 373-(diethylamindcarbonylmethyloxy)phenyl 4-F H 410 383-(4-methylpiperazin-1-ylcarbonylmethyloxy)phenyl 4-F H 437 393-(2-dimethylaminoethoxy)phenyl 4-F H 368 403-(methylcarbonylmethyloxy)phenyl 4-F H 353 413-[4-(2-hydroxyethyl)piperazin-1-ylcarbonylmethyloxy]-phenyl 4-F H 46742 3-[3-(RS)-hydroxypyrrolidin-1-ylcarbonylmethyloxy]-phenyl 4-F H 43843 3-aminophenyl 4-F H 165.2-165.8 44 3-(3-imidazol-1-ylpropoxy)phenyl4-F H 405 45 3-[3-(4-(RS)-hydroxypiperidin-1-yl)propoxy]phenyl 4-F H 43846 3-(piperazin-1-yl)phenyl 4-F.2HCl H 163.2-163.6 473-(2-aminoethyl)phenyl 4-F.HCl H 240.6-240.8 483-[3-(morpholin-4-yl)propylamino]phenyl 4-F H 423 493-[2-(morpholin-4-yl)ethylamino]phenyl 4-F H 409 503-(2-aminosulfonylethyl)phenyl 4-F H   170-170.4 513-(piperidin-3-yl)phenyl 4-F H 222.4-223   523-(3-dimethylaminopropylamino)phenyl 4-F H 381 533-[2-(3-(RS)-hydroxypyrrolidin-1-yl)ethylamino]phenyl 4-F H 423 543-(2-hydroxyethoxy)phenyl 4-F H 341 553-[3-(morpholin-4-yl)prop-1-ynyl]phenyl 2-F 4-F 190.4-191.2 563-[3-(morpholin-4-yl)propyl]phenyl 2-F 4-F 226.4-227.5 573-(2-aminopyridin-5-yl)phenyl 2-F.HCl 4-F 281.2-281.6 583-(pyrimidin-3-yl)phenyl 4-F H 237-241 593-(1-methylpyridin-3-yl)phenyl.iodide 4-F H 191.1-192.4 603-(N-oxidopyridin-3-yl)phenyl 2-F 4-F 251.1-251.7 613-(pyridin-4-yl)phenyl 2-F.HCl 4-F 218-226 376 623-(2-aminopyrimidin-5-yl)phenyl 2-F.HCl 4-F 272-275 633-(2-amino-6-methylpyridin-5-yl)phenyl 2-F.HCl 4-F 215-217 643-(6-methylpyridin-2-yl)phenyl 2-F.HCl 4-F 268-279 653-(pyridin-3-yl)phenyl 4-MeHCl H 281.3-282.8 66 3-(pyridin-3-yl)phenylH.HCl 3-MeO 256.1-256.5 67 3-(pyridin-3-yl)phenyl 3-HO.HCl H 269-273 683-(pyridin-3-yl)phenyl 4-sulfamoyl H.HCl >300 419 693-(pyridin-3-yl)phenyl 2-Me.HCl 4-Me 250.7-251.8 703-(N-oxidopyridin-3-yl)phenyl 2-Me H 190.5-191.2 713-(N-oxidopyridin-3-yl)phenyl 4-Me H   212-213.5 723-(2,6-dimethylpyridin-3-yl)phenyl 2-F.HCl 4-F >300 440.879 733-(pyridin-3-yl)phenyl 2-Me.HCl 4-Cl 425.317 74 3-(pyridin-3-yl)phenyl3-Me.HCl 4-Me 404.899 75 3-(pyridin-3-yl)phenyl 4- H.HCl 454.936methylsulfonyl 76 3-(pyridin-3-yl)phenyl 2-Et.HCl H 404.899 773-(imidazol-2-yl)phenyl 2-F.HCl 4-F 78 3-(3-ethoxycarbonylphenyl)phenyl4-F H 267.4-268.7 79 3-(pyridin-3-yl)phenyl 4-OH.HCl H 803-(3-carboxyphenyl)phenyl 4-F H 117-128 429 813-{2-(piperidin-1-ylethoxy)}phenyl 4-F.HCl H 210.2-211.2 823-(pyridin-2-ylmethoxy)phenyl 4-F H 176.1-177.3 833-isopropylaminocarbonyloxyphenyl 4-F H 225.2-230.1 843-ethylaminocarbonyloxyphenyl 4-F H 201.2-202.8 853-(1,2-dihydroxyethyl)phenyl 4-F H 52-56 341.34 863-(1-piperidinylmethyl)phenyl 2-F 4-F 116.6-118.6 396.439 873-(3-hydroxy-3-methyl-but-1-ynyl)phenyl 4-F H 152.6-153.1 883-(3-pyridylethynyl)phenyl 2-F 4-F 183.5-184.0 893-{3-(S,S-dioxo-thiomorpholin-4-yl)-1-propynyl}phenyl 2-F 4-F190.1-191.2 90 3-(3-hydroxy-3-methylbutyl)phenyl 4-F H 101.3-102.8 913-(3-pyridylethyl)phenyl 2-F 4-F 153.4-153.7 923-{3-(S,S-dioxo-thiomorpholin-4-yl)propyl}phenyl 2-F 4-F 123.8-125.9 933-{2-(1-hydroxycyclopentyl)ethyl}phenyl 4-F H 128.4-129.7 943-{2-(1-hydroxycyclopentyl)ethynyl}phenyl 2-F 4-F 176.8-177.1 953-{2-(1-hydroxycyclopentyl)ethyl}phenyl 2-F 4-F 120.3-121   963-(3-hydroxybutyl)phenyl 2-F 4-F 111.1-112.6 973-{2-(morpholin-4-yl)ethoxy}phenyl 2-F H 130.8-135.1 983-(2-(morpholin-4-yl)ethoxy}phenyl 2-Cl 6-Cl 144.2-145.1 993-(pyridin-3-yl)phenyl 2-F.HCl 4-F 256.5-257.7 1003-(2-methylsulfonylethyl)phenyl 4-F H 151.5-155.6 1013-(2-methylsulfonylethyl)phenyl 2-F 4-F 157.2-157.7 1023-(2-ethylsulfonylethenyl)phenyl 2-F 4-F 101.6-105.6 1033-(1,2-dihydroxyethyl)phenyl 2-F 4-F 59-64 1043-(2,2-dimethyl-1,3-dioxalan-5-yl)phenyl 4-F H 94.5-100  1053-hydroxymethylphenyl 2-F 4-F 155.4-156.5 1063-[2(R),3-dihydroxypropoxy]phenyl 4-F H 150.2-153.0 1073-[2(S),3-dihydroxypropoxy]phenyl 4-F H 149.9-153.0 1083-(2-hydroxyethylsulfonyl)phenyl 2-F 4-F 92.1-93.8 1093-(1,2-dihydroxyethyl)phenyl 2-Me H 83.0-85.5 1103-[2-(N-oxidomorpholin-4-yl)ethoxy]phenyl 4-F H      185-186dec 1113-[2-(morpholin-4-yl)ethoxylphenyl 2-F 6-F 178.9-181.2 1123-(2,3-dihydroxypropyl)phenyl 2-F 4-F 140-142 1133-(2-hydroxyethoxy)phenyl 4-F H 165.3-166.7 114 2-thienyl 4-F H 287 1152-furyl 4-F H 271 116 2-methyl-3-furyl 2-F 4-F 117 6 quinolinyl 2-F 4-F  220-259.2 118 2-hydroxyethylphenyl 4-F H 154.5-155.0 1193-carboxymethyloxyphenyl 4-F H 215.9-216.2 120 3-(pyridin-3-yl)phenyl2-Me H 223.7-225.1 146 3-(3-sulfamoylphenyl)phenyl 4-F H 214.6-217.5 1473-(3-methylsulfonylphenyl)phenyl 4-F H 148 3-methylsulfonylmethylphenyl4-F H 373 149 3-sulfamoylmethylphenyl 4-F H 150 3-carboxymethylphenyl4-F H 151 3-(2-hydroxyethylsulfonyl)phenyl 4-F H 1523-[(2,2-dimethyl-1,3-dioxalan-5-yl-methoxy]phenyl 4-F H 1533-oxiranylmethoxyphenyl 4-F H 154 3-[2(R),3-dihydroxypropoxy]phenyl 2-F4-F 115.6-116.9 155 3-[2(R),3-dihydroxypropoxy]phenyl 2-Me H 368 (M + H)156 3-[2(R),3-dihydroxy-3,3-dimethylpropoxy]phenyl 4-F H 433 1573-[2(R),3(R)-dihydroxy-3-methylpropoxy]phenyl 4-F H 1583-[2(R),3(S)-dihydroxy-3-methylpropoxy]phenyl 4-F H 1593-[2(S),3(S)-dihydroxy-3-methylpropoxy]phenyl 4-F H 1603-[2(S),3(R)-dihydroxy-3-methylpropoxy]phenyl 4-F H 1613-[2(R),3-dihydroxy-3,3-dimethylpropoxy]phenyl 4-F H 1623-[2(S),3-dihydroxy-3,3-dimethylpropoxy]phenyl 4-F H 1633-[3,4-dihydroxycyclopentyloxy]phenyl 4-F H 1643-[2-(1,3-dihydroxy)propoxy]phenyl 4-F H

PREFERRED EMBODIMENTS

While the broadest definition of this invention is set forth in theSummary of the Invention, certain compounds of Formula (I) arepreferred. For example,

(I) A preferred group of compounds is that wherein R³ is selected from:

(a) optionally substituted heterocyclyl;

(b) aryl or heteroaryl both optionally substituted with a substituentselected from halo, alkyl, amino, alkoxy, carboxy, lower alkoxycarbonyl, SO₂R′ (where R′ is alkyl) or SO₂NHR′R″ (where R′ and R″ areindependently hydrogen or alkyl);

(c) heteroalkyl;

(d) heteroalkenyl;

(e) heteroalkylamino;

(f) heteroalkoxy;

(g) optionally substituted heterocyclylalkyl or heterocyclyloxy;

(h) optionally substituted heterocyclylalkenyl;

(i) optionally substituted heterocyclylalyyl;

(j) optionally substituted heterocyclylalkoxy;

(k) optionally substituted heterocyclylalkylano;

(l) optionally substituted heterocyclylalkylcarbonyl;

(k) —Y—(alkylene)—R⁹ where Y is a single bond, —O— or —NH— and R⁹ isoptionally substituted heteroaryl, —CONR¹²R¹³, SO₂NR¹⁴, —SO₂NR¹⁵R¹⁶—NHSO₂R¹⁷ or —NHSO₂NR¹⁸R¹⁹ where R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ R¹⁷, R¹⁸ andR¹⁹ are independently of each other hydrogen, alkyl or heteroalkyl;

(l) cycloalkylalkyl, cycloalkylalkynyl and cycloalkylalkynyl, alloptionally substituted with alkyl, halo, hydroxy or amino;

(m) arylaminoalkylene or heteroarylaminoalkylene; or

(n) Z-alkylene-NR³⁰R³¹ where Z is —NH—, —N(alkyl)— or —O—, and R³⁰ andR³¹ are independently of each other, hydrogen, alkyl or heteroalkyl.

Within the above preferred group, more preferred groups of compounds arethose wherein, A and B are aryl, preferably phenyl.

Within the above preferred and more preferred groups, an even morepreferred group of compounds is that wherein:

R′ is hydrogen;

R² is hydrogen or alkyl, preferably hydrogen or methyl, more preferablyhydrogen.

R⁴ is hydrogen, halo or alkyl, preferably hydrogen, chloro, fluoro ormethyl, more preferably hydrogen.

Within the above preferred and more preferred groups, a particularlypreferred group of compounds is that wherein R³ is at the 3-position andis optionally substituted heteroaryl, preferably pyridinyl,N-oxidopyridinyl or pyridonyl.

Another particularly preferred group of compounds is that wherein R³ isat the 3-position and is optionally substituted phenyl, preferablysulfamoylphenyl, alkylsulfamoylphenyl, carboxyphenyl, carboxamidophenyl,alkoxycarbonylphenyl, alkylaminocarbonylphenyl ordialkylaminocarbonylphenyl.

A third particularly preferred group of compounds is that wherein:

R³ is at the 3-position and is selected from:

(a) heteroalkyl;

(b) heteroalkoxy;

(c) heteroalkylamino;

(d) optionally substituted heterocyclylalkyl;

(e) optionally substituted heterocyclylalkoxy;

(f) optionally substituted heterocyclylalkylamino;

(g) —Y—(alkylene)—R⁹ where Y is a single bond, —O— or —NH— and R⁹ isoptionally substituted heteroaryl, —CONR¹²R¹³, SO₂R¹⁴,—SO₂NR¹⁵R¹⁶—NHSO₂R¹⁷ or —NHSO₂NR¹⁸R¹⁹ where R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ R¹⁷,R¹⁸ and R¹⁹ are independently of each other hydrogen, alkyl orheteroalkyl; or

(h) Z-alkylene-NR³⁰R³¹ where Z is —NH—, —N(alkyl)— or —O—, and R³⁰ and

R³¹ are independently of each other, hydrogen, alkyl or heteroalkyl.

Preferred groups for R³ include amino, 3-dimethylaminopropoxy,2-dimethylaminoethoxy, 2-dimethylaminoethyl, 3-dimethylaminopropyl,4-dimethylaminobutyl, 2-dimethylaminoethylamino,3-dimethylaminopropylamino, 3-dimethylaminoprop-1-enyl,3-dimethylaminoprop-1-ynyl and 2-dimethylaminoethylcarbonyl, preferablyamino.

Another group of preferred groups for R³ is selected from3-(morpholin-4-yl)propoxy, 2-(morpholin-4-yl)ethoxy,3-(morpholin4-yl)propyl, 2-(morpholin-4-yl)ethyl,4-(morpholin-4-yl)butyl, 3-(morpholin-4-yl)propylamino,2-(morpholin-4-yl)-ethylamino, 3-(morpholin-4-yl)-prop-1-enyl,3-(morpholin-4-yl)prop-1-ynyl, 4-methylpiperazin-1-yl, piperazin-1-yl,pyridin-3-yl, morpholin-4-ylmethylcarbonyl, 3-dimethylaminoprop-1-enyl,3-dimethylaminoprop-1-ynyl, 2-aminosulfonylethyl,2-aminosulfonylethenyl, acetylamino and trifluoroacetylamino, preferably2-(morpholin-4-yl)ethoxy and 3-(morpholin-4-yl)-propyl.

A fourth group of particularly preferred compounds is that where R⁵ ishalo or alkyl and R⁶ is hydrogen, halo or alkyl, preferably R⁵ is 4-F or2-Me and R⁶ is hydrogen, or R⁵ is 2-F and R⁶ is 4-F.

Exemplary particularly preferred compounds are:

5-amino-1-(4-fluorophenyl)-4-[3-(2-morpholin-4-ylethoxy)benzoyl]pyrazole.

5-amino-1-(2,4-difluorophenyl)-4-[3-(3-morpholin-4-ylpropyl)benzoyl]pyrazole.

5-amino-4-(3-aminobenzoyl)-1-(4-fluorophenyl)pyrazole.

5-amino-1-(4-fluorophenyl)-4-[3-(3-morpholin-4-ylpropyl)benzoyl]pyrazole.

5-amino-4-[3-(2-aminosulfonylethenyl)benzoyl]-1-(4-fluorophenyl)pyrazole.

5-amino-4-(3-acetylaminobenzoyl)-1-phenylpyrazole.

5-amino-4-[3-(2-aminoethyl)benzoyl]-1-(4-fluorophenyl)pyrazole.

5-amino-1-(4-fluorophenyl)-4-[3-(3-morpholin-4-ylpropylamino)benzoyl]pyrazole.

5-amino-4-[3-(2-aminosulfonylethyl)benzoyl]-1-(4-fluorophenyl)pyrazole.

5-amino-1-(4-fluorophenyl)-4-[3-(pyridin-3-yl)benzoyl]pyrazole.

5-amino-1-(2-methylphenyl)-4-[3-(pyridin-3-yl)benzoyl]pyrazole.

5-amino-1-(2-methylphenyl)-4-[3-(N-oxidopyridin-3-yl)benzoyl]pyrazole.

5-amino-4-[3-(2,3-dihydroxypropoxy)benzoyl]-1-(4-fluorophenyl)pyrazole.

5-amino-4-[3-(1,2-dihydroxyethyl)benzoyl]-1-(4-fluorophenyl)pyrazole.

5-amino-1-(4-fluorophenyl)-4-[3-sulfamoylbenzoyl]pyrazole.

GENERAL SYNTHETIC SCHEME

Compounds of this invention can be made by the methods depicted in thereaction schemes shown below.

The starting materials and reagents used in preparing these compoundsare either available from commercial suppliers such as Aldrich ChemicalCo., (Milwaukee, Wis., USA), Bachem (Torrance, Calif., USA),Emka-Chemie, or Sigma (St. Louis, Mo., USA) or are prepared by methodsknown to those skilled in the art following procedures set forth inreferences such as Fieser and Fieser's Reagents for Organic Synthesis,Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of CarbonCompounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers,1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991),March's Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition),and Larock's Comprehensive Organic Transformations (VCH Publishers Inc.,1989). These schemes are merely illustrative of some methods by whichthe compounds of this invention can be synthesized, and variousmodifications to these schemes can be made and will be suggested to oneskilled in the art having referred to this disclosure.

The starting materials and the intermediates of the reaction may beisolated and purified if desired using conventional techniques,including but not limited to filtration, distillation, crystallization,chromatography, and the like. Such materials may be characterized usingconventional means, including physical constants and spectral data.

Preparation of Compounds of Formula (I)

Schemes A, B and C describe methods to generate the compounds of Formula(I).

In general, compounds of Formula (I) can be prepared by following eithermethod (a) or (b) as described below.

Method (a)

Reaction of a 2-ketoacetonitrile of formula 1 [where Z is halo (e.g.,bromo or iodo), alkoxy, nitro or acetylamino] withN,N-diphenylformamidine gives a 2-keto-3-phenylamino-acrylonitrile offormula 2. The reaction occurs upon heating in a high boiling aromatichydrocarbon such as toluene, xylene, and the like.

In general, compounds of formula 1 are either commercially available orthey can be prepared by methods well known in the art. For example,2-aroylacetonitriles of formula 1 such as 4-methoxybenzoylacetonitrile,3-nitrobenzoylacetonitrile are commercially available. Others can beprepared by treating acetonitrile with a base such as n-butyllithiumfollowed by reaction of the formed acetonitrile anion with anaroyl/heteroaroyl halide or an aryl/heteroaryl ester as described inSjogren, E. B., et al., J. Med. Chem, 34, 3295, (1991).

Reaction of the 2-keto-3-phenylaminoacrylonitrile of formula 2 with ahydrazine of formula 3 provides a 5-amino-4-ketopyrazole of formula 4.This reaction is generally carried out in a polar solvent such asethanol, isopropanol, and the like. Aryl/heteroaryl hydrazines offormula 2 such as 2- or 3-chlorophenylhydrazine, 2-,3-, or4-fluorophenylhydrazine, phenylhydrazine, 2-hydrazinopyridine,2-hydrazinobenzothiazole, 2-hydrazinoquinoline etc., are commerciallyavailable.

Compound 4 is then converted to a compound of Formula (I) where R¹ ishydrogen and R³ is as defined in the Summary of the Invention by methodswell known in the art. Some such procedures are described below.

(i) A compound of Formula (I) where R³ is heterocyclylalkyloxy can beprepared from a compound of formula 4 where Z is alkoxy as shown below:

A compound of Formula (I) where R³ is heterocyclylalkloxy can beprepared from a compound of formula 4 where Z is alkoxy by firstde-alkylating the alkoxy group to give the corresponding compound offormula 5 where Z is hydroxy followed by reaction with aheterocyclylalkyl halide [e.g., 4-(2-chloroethyl)morpholine,1-(2-chloroethyl)pyrrolidine, and the like]. The de-alkylation reactionis carried out either with boron tribromide in a halogenated organicsolvent such as dichloromethane or by heating 4 in neat pyridiniumhydrochloride. The alkylation is carried out in the presence of a base(such as potassium carbonate, cesium carbonate, and the like) in a polarorganic solvent such as acetonitrile, dimethylformamide, acetone, andthe like.

Alternatively, a heterocyclylalkyl group can be attached by reacting 5with an alkyl dihalide followed by the reaction of the resultinghaloalkyloxy intermediate with a heterocyclyl group (e.g., piperazine,morpholine, pyrrolidine, and the like) under the reaction conditionsdescribed above. Alkyl dihalides such as 1-bromo-2-chloroethane,1-chloro-3-iodopropane, and the like, are commercially available.

(ii) A compound of Formula (I) where R³ is —O—(alkylene)—R⁹ (where R⁹ is—COOH, —COR¹⁰, —COOR¹¹ or —CONR¹²R¹³) can be prepared from a compound offormula 5 as shown below:

A compound of Formula (I) where R³ is —O—(alkylene)—COOR¹¹ is preparedby reacting a compound of formula 5 with an alkylating agent of formulaX—(alkylene)—CO₂R¹¹ where X is a halo group. Hydrolysis of the estergroup provides the free acid (R⁹ is —COOH) which can be converted to acompound of Formula (I) where R⁹=—CONR¹²R¹³, if desired, by treating theacid with an amine of formula NR¹²R¹³ (where R¹² and R¹³ are as definedin the Summary of the Invention) in the presence of a suitable couplingagent (e.g., carbonyl diimidazole, N,N-dicyclohexylcarbodiimide and thelike).

A compound of Formula (I) where R⁹ is —COR¹⁰ can be prepared from acompound of Formula (I) where R⁹ is —COOH by first converting the acidto a Weinreb amide followed by treatment with either a Grignard reagentor organolithium reagent of formula R¹⁰MgBr or R¹⁰Li, respectively.

(iii) A compound of Formula (I) where R³ is —NH—(alkylene)—R⁹ where R⁹is —COOH, —COR¹⁰, —COOR¹¹, —CONR¹²R¹³ or heterocyclylalkylamino can beprepared from a compound of formula 4 where Z is a nitro group byreducing the nitro group to the amino group and then following theprocedures described above.

(iv) A compound of Formula (I) where R³ is heteroalkenyl, heteroalkynyl,heterocyclylalkenyl, heterocyclylalkynyl, heteroalkyl orheterocyclylalkyl can be prepared as shown below.

A compound of Formula (I) where R³ is heteroalkenyl, heteroalkynyl,heterocyclylalkenyl or heterocyclylalkynyl can be prepared by reacting acompound of formula 4 where Z is halo with a heteroalkene, heteroalkyne,heterocyclylalkene or heterocyclylalkyne respectively in the presence ofa palladium (II) catalyst such asdichlorobis(triphenylphosphine)-palladium (II) in an organic base suchas diisopropylamine, and the like. Heteroalkenes, heteroalkynes such asallyl alcohol, propargyl alcohol, 3-butyn-1-ol, propargylamine arecommercially available. Heterocyclylalkyne can be prepared by reactingan alkynyl halide with a heterocycle. For example,2-morpholin-1-ylprop-1-yne can be prepared by reacting propargyl bromidewith morpholine. Reduction of the double or triple bond under catalytichydrogenation reaction conditions provides the corresponding compound ofFormula (I) where R³is a heterocyclylalkyl or heteroalkyl group.

(v) A compound of Formula (D) where R³ is —NHSO₂R⁶, —NHSO₂NR⁷R⁸ orNHC(X)R²³R²⁴ (where X is —O— or —S—) can be prepared from a compound ofFormula (I) where R³ is amino by following the synthetic proceduresdescribed in PCT Application No. WO 97/46524.

A compound of Formula (I) where R¹ is an acyl group can be prepared byreacting the the corresponding compound of Formula (I) where R¹ ishydrogen with an acylating reagent of formula R¹COL where L is a leavinggroup under acylating reaction conditions such as halo. The reaction iscarried out in the presence of a base such as sodium hydroxide, cesiumcarbonate, and the like.

Method (b)

Alternatively, a compound of Formula (I) can be prepared from an esterof formula 6 where Z is as defined above, by first converting the Zgroup in compound 6 to the desired R³ group utilizing the reactionconditions described in method (a)(i-v) above. Condensation of 7 withacetonitrile anion gives a 2-ketoacetonitrile of formula 8 which is thenconverted to a compound of Formula (I) utilizing the reaction conditionsdescribed in method (a) above.

Compounds of Formula (I) where R² is thioalkyl or alkyl can be preparedby following the procedures described in U.S. Pat. No. 5,712,303.

Condensation of 2-cyano-3-ethoxyacrylate of formula 9 with a hydrazineof formula 3 provides a 5-amino-4-ethoxycarbonyl pyrazole of formula 10.The condensation reaction is carried out in a suitable polar organicsolvent such as ethanol, isopropanol, and the like. Hydrolysis of 10with an aqueous base (e.g., sodium hydroxide, lithium hydroxide, and thelike) in an alcoholic organic solvent (e.g., methanol, ethanol, and thelike) provides the corresponding 5-amino-4-carboxypyrazole of formula11. Treatment of 11 with dipyridyldisulfide followed by reaction of theresulting thiopyridyl ester derivative 12 with an organometallic reagentsuch as a Grignard reagent or an organolithium reagent shown aboveprovides a compound of Formula (I).

Thermal decarboxylation of a 5-amino-4-carboxypyrazole of formula 11gives the corresponding 5-aminopyrazole of formula 13. Compound 13 isthen converted to a compound of Formula (I) as shown in method (a) or(b) above.

In method (a), a compound of formula 13 is converted to a compound ofFormula (I) by first protecting the amino group in compound 13 with asuitable amino protecting group (e.g., tert-butoxycarbonyl, and thelike) to give the corresponding amino-protected compound of formula 14.Treatment of 14 with an acid derivative of formula R³COL where L is aleaving group under organometallic displacement reaction conditions[e.g., alkoxy (preferably methoxy or ethoxy), dialkylamino, orpreferably N,O-dimethylhydroxylamino] followed by the removal of theamino protecting group then provides a compound of Formula (I). Thenucleophilic substitution is carried out in the presence of 2equivalents of an alkyllithium (e.g., tert-butyllithium, and the like)and in an aprotic organic solvent such as tetrahydrofuran. The reactionconditions employed for the removal of the amino protecting groupdepends on the nature of the protecting group. For example, iftert-butoxycarbonyl is the protecting group, it is removed by treatmentwith an acid such as trifluroacetic acid, hydrochloric acid, and thelike.

Acid derivatives of formula R³COL can be prepared by methods well knownin the field of organic chemistry. For example, an acid derivative whereL is a N,O-dimethylhydroxylamino group can be prepared from itscorresponding acid by first converting the acid to the acid chloridewith a suitable chlorinating agent such as oxalyl chloride, followed bytreatment with N,O-dimethylhydroxylamine hydrochloride in the presenceof an organic base such as triethylamine.

In method (b), a compound of formula 10 is brominated to give the5-amino-4-bromopyrazole of formula 15. The bromination reaction iscarried out with a suitable brominating agent such as N-bromosuccinimidein a suitable polar organic solvent such as dimethylformamide. Compound15 is then converted to a compound of Formula (I) utilizing the reactionconditions described in Scheme C, method (a) above.

UTILITY, TESTING, AND ADMINISTRATION Utility

The compounds of Formula (I) are p38 MAP kinase inhibitors and thereforecompounds of Formula (I) and compositions containing them are useful inthe treatment of diseases such as rheumatoid arthritis, osteoarthritis,spondylitis, bone resorption diseases, sepsis, septic shock, toxic shocksyndrome, endotoxic shock, tuberculosis, atherosclerosis, diabetes,adult respiratory distress syndrome, chronic pulmonary inflammatorydisease, fever, periodontal diseases, ulcerative colitis, pyresis,Alzheimer's and Parkinson's diseases.

Testing

The ability of the compounds of Formula (I) to inhibit p38 MAP kinasewas demonstrated by the in vitro assay described in Example 15. Theability of the compounds of Formula (I) to inhibit the release of TNF-αwas demonstrated by the in vitro and the in vivo assays described indetail in Examples 16 and 17, respectively. The anti-inflammatoryactivity of the compounds of this invention was determined utilizingadjuvant induced arthritis in rats assay described in Example 18.

Administration and Pharmaceutical Compositions

In general, the compounds of this invention will be administered in atherapeutically effective amount by any of the accepted modes ofadministration for agents that serve similar utilities. The actualamount of the compound of this invention, i.e., the active ingredient,will depend upon numerous factors such as the severity of the disease tobe treated, the age and relative health of the subject, the potency ofthe compound used, the route and form of administration, and otherfactors.

Therapeutically effective amounts of compounds of Formula (I) may rangefrom approximately 0.1-50 mg per kilogram body weight of the recipientper day; preferably about 1-30 mg/kg/day. Thus, for administration to a70 kg person, the dosage range would most preferably be about 70 mg to2.1 g per day.

In general, compounds of this invention will be administered aspharmaceutical compositions by any one of the following routes: oral,systemic (e.g., transdermal, intranasal or by suppository), orparenteral (e.g., intramuscular, intravenous or subcutaneous)administration. The preferred manner of administration is oral using aconvenient daily dosage regimen which can be adjusted according to thedegree of affliction. Compositions can take the form of tablets, pills,capsules, semisolids, powders, sustained release formulations,solutions, suspensions, elixirs, aerosols, or any other appropriatecompositions.

The choice of formulation depends on various factors such as the mode ofdrug administration (e.g., for oral administration, formulations in theform of tablets, pills or capsules are preferred) and thebioavailability of the drug substance. Recently, pharmaceuticalformulations have been developed especially for drugs that show poorbioavailability based upon the principle that bioavailability can beincreased by increasing the surface area i.e., decreasing particle size.For example, U.S. Pat. No. 4,107,288 describes a pharmaceuticalformulation having particles in the size range from 10 to 1,000 nm inwhich the active material is supported on a crosslinked matrix ofmacromolecules. U.S. Pat. No. 5,145,684 describes the production of apharmaceutical formulation in which the drug substance is pulverized tonanoparticles (average particle size of 400 nm) in the presence of asurface modifier and then dispersed in a liquid medium to give apharmaceutical formulation that exhibits remarkably highbioavailability.

The compositions are comprised of in general, a compound of Formula (I)in combination with at least one pharmaceutically acceptable excipient.Acceptable excipients are non-toxic, aid administration, and do notadversely affect the therapeutic benefit of the compound of Formula (I).Such excipient may be any solid, liquid, semi-solid or, in the case ofan aerosol composition, gaseous excipient that is generally available toone of skill in the art.

Solid pharmaceutical excipients include starch, cellulose, talc,glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silicagel, magnesium stearate, sodium stearate, glycerol monostearate, sodiumchloride, dried skim milk and the like. Liquid and semisolid excipientsmay be selected from glycerol, propylene glycol, water, ethanol andvarious oils, including those of petroleum, animal, vegetable orsynthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesameoil, etc. Preferred liquid carriers, particularly for injectablesolutions, include water, saline, aqueous dextrose, and glycols.

Compressed gases may be used to disperse a compound of this invention inaerosol form. Inert gases suitable for this purpose are nitrogen, carbondioxide, etc.

Other suitable pharmaceutical excipients and their formulations aredescribed in Remington's Pharmaceutical Sciences, edited by E. W. Martin(Mack Publishing Company, 18th ed., 1990).

The amount of the compound in a formulation can vary within the fullrange employed by those skilled in the art. Typically, the formulationwill contain, on a weight percent (wt %) basis, from about 0.01-99.99 wt% of a compound of Formula (I) based on the total formulation, with thebalance being one or more suitable pharmaceutical excipients.Preferably, the compound is present at a level of about 1-80 wt %.Representative pharmaceutical formulations containing a compound ofFormula (I) are described in Example 14.

EXAMPLES

The following preparations and examples are given to enable thoseskilled in the art to more clearly understand and to practice thepresent invention. They should not be considered as limiting the scopeof the invention, but merely as being illustrative and representativethereof. Numbers in brackets refer to the CPD # in Table I.

Example 15-Amino-1-(4-fluorophenyl)-4-[3-{3-(morpholin-4-yl)prop-1-ynyl}benzoyl]pyrazole(3)

Step 1

n-Butyllithium (214 ml, 340 mmol, 1.6 M solution in hexane) was addeddropwise to a solution of acetonitrile (23.8 ml, 460 mmol) in drytetrahydrofuran (1000 ml) at −78° C. After stirring the reaction mixturefor 20 min., a solution of 4-bromobenzoyl chloride in drytetrahydrofuran (50 ml) was added dropwise over 20 min. After 1 h,saturated ammonium chloride was added (200 ml) and the reaction mixturewas allowed to wann to room temperature. The product was extracted intoether and washed with 1N hydrochloric acid (400 ml). The organics wereremoved in vacuo and the residue was redissolved in ethyl acetate.Ammonium hydroxide was added to give a solid which was filtered,redissolved in ethyl acetate and washed with 2 N hydrochloric acid. Theorganic layer was washed with brine, dried over sodium sulfate andconcentrated in vacuo to give 2-(3-bromobenzoyl)-acetonitrile (16.6 g)as a solid.

Step 2

A mixture of 2-(3-bromobenzoyl)acetonitrile (16.5 g, 73.6 mmol) andN,N-diphenylformamidine (14.5 g, 73.6 mmol) in xylene (100 ml) washeated at reflux under a nitrogen atmosphere. After 3 h, the reactionmixture was cooled to room temperature and diluted with ether to give2-(3-bromobenzoyl)-3-phenylaminoacrylonitrile (17.9 g) as a solid.

Step 3

A mixture of 4-fluorophenylhydrazine (4.25 g, 33.7 mmol) and2-(3-bromobenzoyl)-3-phenylaminoacrylonitrile (10.0 g, 30.7 mmol) inethanol (100 ml) was heated at reflux under a nitrogen atmosphere. After4 h, the reaction mixture was cooled to room temperature, diluted withhexane to give 5-amino-4-(3-bromobenzoyl)-1-(4-fluorophenyl)pyrazole(9.7 g) as a solid.

Replacing 4-fluorophenylhydrazine with 2,4-difluorophenylhydrazine instep 3 above gave5-amino-4-(3-bromobenzoyl)-1-(2,4-difluorophenyl)pyrazole.

Step 4

A mixture of 5-amino-4-(3-bromobenzoyl)-1-(4-fluorophenyl)pyrazole (1.3g, 4.16 mmol), 4-(prop-2-ynyl)morpholine (2.1 g, 16.6 mmol) [prepared byadding to a solution of morpholine (14.7 ml, 168 mmol) in ether (50 ml),propargyl bromide (7.5 ml, 84 mmol) in ether (50 ml) dropwise over 30min. and heating the reaction mixture to reflux. After 16 h, thereaction mixture was cooled to room temperature and filtered through aBuchner funnel. The filtrate was concentrated and purified by flashchromatography (gradient elution, 20-100% EtOAc/hexane) to give4-(prop-2-ynyl)morpholine (5.0 g)], bis(triphenylphosphine)-palladiumchloride (0.29 g, 0.42 mmol) and copper iodide (0.079 g, 0.42 mmol) indiisopropylamine (60 ml) was heated at 70° C. under argon. After 10 h,the reaction mixture was cooled to room temperature, diluted with ethylacetate, washed with brine and dried over sodium sulfate. The organicswere removed in vacuo. The crude product was purified by flashchromatography (elution gradient, EtOAc-5% MeOH/EtOAc with 0.2% NH₄OH)to give5-amino-1-(4-fluorophenyl)-4-[3-(3-morpholin-4-ylprop-1-ynyl)benzoyl]-pyrazolewhich was converted to the hydrochloride salt and recrystallized from amixture of methanol/ethyl acetate/hexane to give (1.4 g) of the pureproduct.

Proceeding as described in Example 1 above but substituting4-(prop-2-ynyl)-morpholine in Step 4 with:

1-(prop-2-ynyl)-4-methylpiperazine,

1-(prop-2-ynyl)piperidine,

2-propyn-1-ol,

1-dimethylamino-2-propyne, and

2-methyl-3-butyn-2-ol; gave

5-amino-1-(4-fluorophenyl)-4-{3-[3-(4-methylpiperazin-1-yl)prop-1-ynyl]benzoyl}pyrazole.2HCl(8),

5-amino-1-(4-fluorophenyl)-4-[3-{3-(piperidin-1-yl)prop-1-ynyl}benzoyl]pyrazole.HCl(9),

5-amino-1-(4-fluorophenyl)-4-[3-(3-hydroxyprop-1-ynyl)benzoyl]pyrazole(7),

5-amino-4-[3-(3-dimethylaminoprop-1-ynyl)benzoyl]-1-(4-fluorophenyl)pyrazole.HCl(12), and

5-amino-1-(4-fluorophenyl)-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)benzoyl]pyrazole(87), respectively.

Proceeding as described in Example 1 above but substituting4-fluorophenylhydrazine in Step 3 with 2,4-difluorophenylhydrazine, and4-(prop-2-ynyl)morpholine in Step 4 with 3-ethynylpyridine gave

5-amino-1-(2,4-difluorophenyl)-4-[3-(3-pyridylethynyl)benzoyl]pyrazole(88), with 3-(S,S-dioxo-thiomorpholin-4-yl)-1-propyne gave

5-amino-1-(2,4-difluorophenyl)-4-[3-{3-(S,S-dioxo-thiomorpholin-4-yl)-1-propynyl}benzoyl]pyrazole(89), and with 1-ethynylcyclopentanol gave

5-amino-1-(2,4-difluorophenyl)-4-[3-{2-(1-hydroxycyclopentyl)ethynyl}benzoyl]pyrazole(94).

Example 25-Amino-1-(4-fluorophenyl)-4-[3-(3-morpholin-4-ylpropyl)benzoyl]-pyrazoleHydrochloride (6)

A mixture of5-amino-1-(4-fluorophenyl)-4-[3-(3-morpholin-4-ylprop-1-ynyl)-benzoyl]pyrazole(0.45 g, 1.0 mmol) [prepared as described in Example 1] and 5% Pd/C(0.07 g) in ethanol (20 ml) was stirred under hydrogen atmosphere. After16 h, the reaction mixture was filtered through Celite® and the filtratewas concentrated in vacuo. The crude product was purified by flashchromatography (elution gradient, EtOAc-15% MeOH/EtOAc with 0.2% NH₄OH).The product was converted to the hydrochloride salt and recrystallizedfrom a mixture of methanol/ethyl acetate to give5-amino-1-(4-fluorophenyl)-4-[3-(3-morpholin-4-ylpropyl)benzoyl]pyrazole.HCl(0.3 g, mpt. 211.9-212.6° C.) as a solid.

Proceeding as described in Example 2 above, but substituting of5-amino-1-(4-fluorophenyl)-4-[3-(3-morpholin-4-ylprop-1-ynyl)benzoyl]pyrazolewith:

5-amino-1-(4-fluorophenyl)-4-{3-[3-(4-methylpiperazin-1-yl)prop-1-ynyl]benzoyl}parazole,

5-amino-1-(4-fluorophenyl)-4-[3-{3-(piperidin-1-yl)prop-1-ynyl}benzoyl]pyrazole,

5-amino-1-(4-fluorophenyl)-4-[3-(3-hydroxyprop-1-ynyl)benzoyl]pyrazole,

5-amino-4-[3-(3-dimethylaminoprop-1-ynyl)benzoyl]-1-(4-fluorophenyl)pyrazole,

5-amino-1-(4-fluorophenyl)-4-[3-(3-hydroxy-3-methyl-1-butynyl)benzoyl]pyrazole,

5-amino-1-(2,4-difluorophenyl)-4-[3-(3-pyridylethynyl)benzoyl]pyrazole,

5-amino-1-(2,4-difluorophenyl)-4-[3-{3-(S,S-dioxo-thiomorpholin-4-yl)-1-propynyl }benzoyl]pyrazole,

5-amiino-1-(4-fluorophenyl)-4-[3-{2-(1-hydroxycyclopentyl)ethynyl}benzoyl]pyrazole,

5-amino-1-(2,4-difluorophenyl)-4-[3-{2-(1-hydroxycyclopentyl)ethynyl}benzoyl]pyrazolegave

5-amino-1-(4-fluorophenyl)-4-{3-[3-(4-methylpiperazin-1-yl)propyl]benzoyl}pyrazole(30);

5-amino-1-(4-fluorophenyl)-4-[3-(3-piperidin-1-ylpropyl)benzoyl]pyrazole(32);

5-amino-1-(4-fluorophenyl)-4-[3-(3-hydroxypropyl)benzoyl]pyrazole;

5-amino-4-[3-(3-dimethylaminopropyl)benzoyl]-1-(4-fluorophenyl)pyrazole;

5-amino-1-(4-fluorophenyl)-4-[3-(3-hydroxy-3-methylbutyl)benzoyl]pyrazole(90),

5-amino-1-(2,4-difluorophenyl)-4-[3-(3-pyridylethyl)benzoyl]pyrazole(91),

5-amino-1-(2,4-difluorophenyl)-4-[3-{3-(S,S-dioxo-thiomorpholin-4-yl)propyl}benzoyl]pyrazole(92),

5-amino-1-(4-fluorophenyl)-4-[3-{2-(1-hydroxycyclopentyl)ethyl}benzoyl]pyrazole(93), and

5-amino-1-(2,4-difluorophenyl)-4-[3-{2-(1-hydroxycyclopentyl)ethyl}benzoyl]pyrazole respectively.

Example 35-Amino-1-(4-fluorophenyl)-4-[3-{2-(morpholin-4-yl)ethoxy}benzoyl]-pyrazoleHydrochloride (14)

Step 1

A mixture of methyl 3-hydroxybenzoate (8.0 g, 56 mmol) and4-(2-chloroethyl)-morpholine hydrochloride (15.7 g, 84 mmol) andpotassium carbonate (11.5 g, 83 mmol) in toluene (50 ml) was heated atreflux. After 4 days, the reaction mixture was cooled to roomtemperature and diluted with ethyl acetate. The organic layer was washedwith water and then extracted with dilute hydrochloric acid. The acidiclayer was separated, basified with 5 N sodium hydroxide and the productwas extracted into ethyl acetate. The organics were removed in vacuo andthe residue was purified by flash chromatography (elution gradient 3%acetone/methylene chloride) to give methyl3-(2-morpholin-4-ylethoxy)benzoate (9.0 g) as an oil.

Step 2

Lithium diisopropylamide (18.8 ml, 37 mmol, 2.0 M solution inheptane/tetrahydrofuran/ethylbenzene) was added dropwise to a solutionof acetonitrile (1.58 g, 37 mmol) in dry tetrahydrofuran (50 ml) at −78°C. After stirring the reaction mixture for 30 min., a solution of methyl3-(2-morpholin4-ylethoxy)benzoate in dry tetrahydrofuran (50 ml) wasadded dropwise over 10 min. After 15 min., water was added and thereaction mixture was allowed to warm to room temperature. The aqueouslayer was separated and acidified with dilute hydrochloric acid to pH 7.The product was extracted into ethyl acetate and washed with water andbrine and dried over magnesium sulfate. The organics were removed invacuo to give 2-[3-(2-morpholin-4-ylethoxy)phenyl]acetonitrile (5.0 g)as an oil which was used in the next step without further purification.

Step 3

A mixture of 2-[3-(2-morpholin-4-ylethoxy)phenyl]acetonitrile (5.0 g)and N,N-diphenylformamidine (5.0 g, 25.5 mmol) in xylene (150 ml) washeated at 100° C. under a nitrogen atmosphere. After 3 h, the reactionmixture was cooled to room temperature and diluted with hexane to give2-[3-(2-morpholin4-ylethoxy)benzoyl]-3-phenylaminoacrylonitrile (5.0 g)as a solid.

Step 4

A mixture of 4-fluorophenylhydrazine (1.0 g, 6.8 mmol) and2-[3-(2-morpholin-4-ylethoxy)-benzoyl]-3-phenylamlinoacrylonitrile (2.0g, 5.3 mmol) in ethanol (30 ml) was heated at reflux under a nitrogenatmosphere. After 6 h, the reaction mixture was cooled to roomtemperature and diluted with water. The product was extracted into ethylacetate and the organic layer was washed with brine, dried over sodiumsulfate and concentrated in vacuo. Purification by flash chromatography(elution gradient: CH₂Cl₂-3%MeOH/CH₂Cl₂) gave5-amino-1-(4-fluorophenyl)-4-[3-(2-morpholin-4-ylethoxy)benzoyl]pyrazolewhich was converted to the hydrochloride salt (0.7 g, mpt. 191.6-192.5°C.).

Replacing 4-fluorophenylhydrazine in Step 4 above with:

2-fluorophenylhydrazine, and

2,6-dichlorophenylhydrazine, respectively were obtained:

5-amino-1-(2-fluorophenyl)-4-[3-(2-morpholin-4-ylethoxy)benzoyl]pyrazole(97), and

5-amino-1-(2,6-dichlorophenyl)-4-[3-(2-morpholin-4-ylethoxy)benzoyl]pyrazole(98).

Example 4 5-Amino-1-(4-fluorophenyl)-4-[3-(pyridin-3-yl)benzoyl]pyrazole(20)

Step 1

A mixture of 5-amino-4-(3-bromobenzoyl)-1-(4-fluorophenyl)pyrazole (0.9g, 2.5 mmol) [prepared as described in Example 1 above],pyridine-3-boronic acid, 1,3-propanediol cyclic ester (0.5 g, 3 mmol),potassium phosphate (0.8 g, 3.73 mmol) and tetrakistriphosphinepalladium (0.3 g, 0.25 mmol) in dioxane (20 ml) was heated at 85° C.under argon. After 16 h, the reaction mixture was cooled to roomtemperature and poured into brine. The product was extracted into ethylacetate, dried over sodium sulfate and filtered. The organic layer wasremoved in vacuo and the residue was purified by flash chromatography(elution gradient: 40-80% ethyl acetate/hexane) to give5-amino-1-(4-fluorophenyl)-4-[3-(pyridin-3-yl)benzoyl]-pyrazole (0.50 g)which was recrystallized from ethyl acetate (mpt. 222.2-223.0).

Treatment of5-amino-1-(4-fluorophenyl)-4-[3-(pyridin-3-yl)benzoyl]-pyrazole withmethyl iodide in ethyl acetate gave5-amnino-1-(4-fluorophenyl)-4-[3-(N-methylpyridinium-3-yl)benzoyl]pyrazoleiodide(59).

Substitution of 5-amino-4-(3-bromobenzoyl)-1-(4-fluorophenyl)pyrazolewith 5-amino-4-(3-bromobenzoyl)-1-(2,4-difluorophenyl)pyrazole in Step 1above followed by conversion to the hydrochloride salt gave5-amino-1-(2,4-difluorophenyl)-4-[3-(pyridin-3-yl)benzoyl]pyrazole.HCl(99).

Example 55-Amino-4-[3-(2-aminosulfonylethyl)benzoyl]-1-(4-fluorophenyl)pyrazole(50)

Step 1

A mixture of 5-amino-4-(3-bromobenzoyl)-1-(4-fluorophenyl)pyrazole (1.5g, 4.14 mmol) [prepared as described in Example 1 above],vinylsulfonamide (1.33 g, 12.4 mmol), bis(triphenylphosphine)palladiumchloride (0.3 g, 0.42 mmol) and triethylamine (6 ml, 43 mmol) indimethylformamide (18 ml) was heated at 100° C. under argon. After 16 h,the reaction mixture was cooled to room temperature and poured into 1 Nhydrochloric acid. The product was extracted into ethyl acetate, washedwith brine, dried over sodium sulfate and filtered. The organic layerwas removed in vacuo and the residue was purified by flashchromatography (elution gradient: 40-80% ethyl acetate/hexane) to give5-amino-4-[3-(2-aminosulfonylethenyl)benzoyl]-1-(4-fluorophenyl)pyrazolewhich was recrystallized from a mixture of methanol/ethyl acetate/hexaneto give 0.78 g of the desired product.

Step 2

A mixture of5-amino-4-[3-(2-aminosulfonylethenyl)benzoyl]-1-(4-fluorophenyl)-pyrazole(2.1 g, 5.43 mmol) and palladium hydroxide (0.6 g) in methanol (150 ml)was shaken in a Parr apparatus under hydrogen atmosphere at 50 psi.After 4 days, the reaction mixture was filtered through Celite® and thefiltrate was concentrated. The residue was purified by flashchromatography (elution gradient: 40-100% ethyl acetate/hexane) to givea crude product which was recrystallized from methanol/ethylacetate/hexane to give5-amino-4-[3-(2-aminosulfonylethyl)benzoyl]-1-(4-fluorophenyl)pyrazole(0.95 g, mpt. 170-170.4° C.) as a solid.

Replacement of vinylsulfonamide in Step 1 above with vinylmethylsulfonegave:

5-amino-4-[3-(2-methylsulfonylethyl)benzoyl]-1-(4-fluorophenyl)pyrazole(100).

Example 65Amino-1-(4-fluorophenyl)-4-[3-(morpholin-4-ylmethylcarbonyl)-benzoyl]pyrazole(18)

Step 1

A mixture of 5-amino-4-(3-bromobenzoyl)-1-(4-fluorophenyl)pyrazole (3.5g, 9.7 mmol) [prepared as described in Example 1 above],tributyl-(1-ethoxyvinyl)tin (4.3 ml, 12.36 mmol) andtetrakis(triphenylphosphine)palladium (1.0 g, 0.87 mmol) indimethylformamide (25 ml) was heated at 95° C. under argon. After 16 h,the reaction mixture was cooled to room temperature and 10% aqueoushydrochloric acid (25 ml) was slowly added. After 30 min., the reactionmixture was diluted with ethyl acetate and filtered through Celite®. Theorganic layer was separated and washed with brine, dried over sodiumsulfate and concentrated in vacuo. The residue was purified by flashchromatography (elution gradient: 10-60% ethyl acetate/hexane) to give5-amino-4-[3-(1-ethoxyvinyl)benzoyl]-1-(4-fluorophenyl)pyrazole whichwas dissolved in tetrahydrofuran (50 ml). 1 N hydrochloric acid (20 ml)was added and the reaction mixture was stirred at room temperature for16 h. The organic layer was separated, washed with brine, dried oversodium sulfate and concentrated in vacuo. The crude product was purifiedby flash chromatography (elution gradient: 20-50% ethyl acetate/hexane)and then was recrystallized from a mixture of ethyl acetate/hexane togive 5-amino-4-[3-acetylbenzoyl]-1-(4-fluorophenyl)pyrazole (2.0 g).

Step 2

To a suspension of copper bromide (2.2 g, 9.85 mmol) in a (1:1) mixtureof ethyl acetate/methylene chloride (100 ml) at reflux was added asolution of 5-amino-4-[3-acetylbenzoyl]-1-(4-fluorophenyl)pyrazole (1.6g, 4.95 mmol) in methylene chloride (25 ml) under nitrogen. After 16 h,the reaction mixture was concentrated and the residue was partitionedbetween aqueous sodium bisulfite and ethyl acetate. The organic layerwas separated, washed with brine, dried over sodium sulfate andconcentrated in vacuo. The residue was purified by flash chromatography(elution gradient: 10-40% ethyl acetate/hexane) to give5-amino-4-[3-(2-bromoacetyl)benzoyl]-l-(4-fluorophenyl)pyrazole (0.47 g)as a solid.

Step 3

To a solution of morpholine (0.25 ml, 2.79 mmol) in dimethylformamide (5ml) was added a solution of5-amino-4-[3-(2-bromoacetyl)benzoyl]-1-(4-fluorophenyl)pyrazole (0.22 g,0.56 mmol) in dimethylformamide (5 ml). After 16 h, the reaction mixturewas poured into brine and the product wag extracted into ethyl acetate.The organic layer was separated, washed with brine, dried over sodiumsulfate and concentrated in vacuo. The residue was purified by flashchromatography (elution gradient: ethyl acetate-10% methanol/ethylacetate) to give5-amino-1-(4-fluorophenyl)-4-[3-(morpholin-4-ylmethylcarbonyl)benzoyl]pyrazole(0.05 g) as a solid.

Example 75-Amino-1-(4-fluorophenyl)-4-[3-(2-hydroxyethyl)benzoyl]pyrazole (118)

Step 1

To a solution of 3-bromophenylacetic acid (10 g, 46.5 mmol) intetrahydrofuran (100 ml) at 0° C. was added diborane (70 ml, 1.0 Msolution in tetrahydrofuran). The reaction mixture was allowed to warmto room temperature. After 16 h, the reaction mixture was cooled to 0°C. and water was added dropwise (50 ml). The organic layer was separatedand washed with brine, dried over sodium sulfate and concentrated invacuo. The residue was purified by flash chromatography (elutiongradient: 40-60% ethyl acetate/hexane) to give3-(2-hydroxyethyl)bromobenzene (9.0 g).

Step 2

To a solution of 3-(2-hydroxyethyl)bromobenzene (4.0 g, 20 mmol) inmethylene chloride (100 ml) at 0° C. was added a solution oftert-butyldimethylsilyl chloride (3.6 g, 24 mmol), dimethylaminopyridine(0.61 g, 5 mmol) and triethylamine (3.6 ml, 25.9 mmol). After 1 h, thereaction mixture was washed with brine, saturated ammonium chloride,dried over sodium sulfate and concentrated in vacuo. The residue waspurified by flash chromatography (elution gradient: 0-10% hexane/ethylacetate) to give 3-(2-tert-butyl-dimethylsiloxyethyl)bromobenzene (6.0g).

Step 3

A mixture of ethyl (ethoxymethylene)cyanoacetate (26 ml, 154 mmol) and4-fluorophenyl hydrazine (19.4 g, 154 mmol) in ethanol (125 ml) washeated at reflux. After 16 h, the reaction mixture was cooled to roomtemperature. The solid was filtered off and dried to give5-amino-4-ethylcarboxy-1-(4-fluorophenyl)pyrazole (28 g) which wassuspended in a mixture of 1 N lithium hydroxide (100 ml) and methanol(250 ml). The reaction mixture was heated at reflux. After 16 h, thereaction mixture was filtered through a sinter funnel and the filtratewas acidified with 2 N hydrochloric acid (65 ml). The solid was filteredoff and dried to give 5-amino-4-carboxy-1-(4-fluorophenyl)pyrazole (21g).

Step 4

A mixture of 5-amino-4-carboxy-1-(4-fluorophenyl)pyrazole (15 g, 68mmol), aldrathiol-2 (14.9 g, 68 mmol) and triphenylphosphine (17.8 g, 68mmol) in acetonitrile (21) was stirred at room temperature. After 16 h,the product was filtered off and dried to give5-amino-1-(4-fluorophenyl)-4-(2-pyridylthiocarboxy)pyrazole (14 g).

Step 5

Into an oven dried flask containing magnesium turnings (0.386 g, 15.9mmol) and tetrahydrofuran (10 ml) was added3-(2-tert-butyldimethylsiloxyethyl)bromobenzene (5.0 g, 15.9 mmol) andthe reaction mixture was heated at reflux. After 3 h, the reactionmixture was cooled to room temperature and5-amino-1-(4-fluorophenyl)-4-(2-pyridylthiocarboxy)pyrazole (2.37 g, 7.6mmol) was added and the stirring was continued for 16 h. The reactionmixture was concentrated in vacuo. The residue was dissolved in ethylacetate and washed with aqueous ammonium chloride and brine and driedover sodium sulfate. The organics were removed in vacuo and the residuewas purified by flash chromatography (elution gradient: 10-30% ethylacetate/hexane) to give5-amino-1-(4-fluorophenyl)-4-[3-(2-tert-butyldimethylsiloxyethyl)benzoyl]pyrazole(1.20 g).

Step 6

To a solution of5-amino-1-(4-fluorophenyl)-4-[3-(2-tert-butyldimethylsiloxyethyl)-benzoyl]pyrazole(1.2 g, 3.0 mmol) in tetrahydrofuran (25 ml) was addedtetrabutylammonium fluoride (3.6 ml, 3.6 mmol, 1 M solution intetrahydrofuran). After 1 h, the reaction mixture was poured into brineand the product was extracted into ethyl acetate. The organic layer wasdried over sodium sulfate, filtered and concentrated in vacuo. Theresidue was purified by flash chromatography (elution gradient: 40-100%ethyl acetate/hexane) to give5-amino-1-(4-fluorophenyl)-4-[3-(2-hydroxyethyl)benzoyl]pyrazole (0.8g).

Example 8 Synthesis of5-Amino-1-(4-fluorophenyl)-4-{3-[4-methylpiperazin-1-yl)ethyl)-benzoyl]pyrazoleDihydrochloride (31)

Step 1

To a solution of5-amino-1-(4-fluorophenyl)-4-[3-(2-hydroxyethyl)benzoyl]pyrazole (0.8 g,2.5 mmol) in pyridine (10 ml) was added methanesulfonyl chloride (0.29ml, 3.7 mmol). After 2 h, the reaction mixture was poured into 2 Nhydrochloric acid (40 ml) and the product was extracted into ethylacetate. The organic layer was washed with brine, dried over sodiumsulfate, filtered and concentrated in vacuo. The residue was purified byflash chromatography (elution gradient: 40-100% ethyl acetate/hexane) togive5-amino-1-(4-fluorophenyl)-4-[3-(2-methanesulfonyloxyethyl)benzoyl]pyrazole(0.87 g).

Step 2

A mixture of5-amino-1-(4-fluorophenyl)-4-[3-(2-methanesulfonyloxyethyl)-benzoyl]pyrazole(0.22 g, 0.55 mmol), N-methylpiperazine (0.18 ml, 1.64 mmol) andpotassium carbonate (0.22 g, 1.64 mmol) in dimethylformaide (10 ml) washeated at 70° C. After 4 h, the reaction mixture was cooled to roomtemperature, poured into water and the product was extracted into ethylacetate. The organic layer was washed with brine, dried over sodiumsulfate, filtered and concentrated in vacuo. The residue was purified byflash chromatography (elution gradient: ethyl acetate- 20%methanol/ethyl acetate) to5-amino-1-(4-fluorophenyl)-4-{3-[4-methylpiperazin-1-yl)ethyl)benzoyl]pyrazolewhich was converted to the hydrochloride salt (mpt. 272.9-273.9).

Example 95-Amino-4-[3-(2-aminoethyl)benzoyl]-1-(4-fluorophenyl)-pyrazoleHydrochloride (47)

Step 1

A mixture of5-amino-1-(4-fluorophenyl)-4-[3-(2-methanesulfonyloxyethyl)-benzoyl]pyrazole(0.40 g, 0.99 mmol), sodium azide (0.19 ml, 2.97 mmol) and potassiumcarbonate (0.41 g, 2.97 mmol) in dimethylformamide (15 ml) was stirredat room temperature. After 16 h, the reaction mixture was poured intobrine and the product was extracted into ethyl acetate. The organiclayer was dried over sodium sulfate, filtered and concentrated in vacuo.The residue was purified by flash chromatography (elution gradient:20-50% ethyl acetate/hexane) to5-amino-1-(4-fluorophenyl)-4-[3-(2-azidoethyl)benzoyl]pyrazole (0.32 g).

Step 2

To a solution of5-amino-1-(4-fluorophenyl)-4-[3-(2-azidoethyl)benzoyl]pyrazole (0.31 g,0.9 mmol) in tetrahydrofuran (15 ml) was added triphenylphosphine (3.55g, 1.36 mmol). After 48 h, the reaction mixture concentrated in vacuo.The residue was dissolved in 2 N sodium hydroxide and the product wasextracted into ethyl acetate. The organic layer was dried over sodiumsulfate, filtered and concentrated in vacuo. The product was convertedto its hydrochloride salt and recrystallized from a mixture ofmethanol-ethyl acetate to give5-amino-4-[3-(2-aminoethyl)benzoyl]-1-(4-fluorophenyl)pyrazolehydrochloride salt (0.22 g).

Example 105-Amino-4-[3-(tert-butoxycarbonylmethyloxy)benzoyl]-1-(4-fluorophenyl)pyrazole

Step 1

Into an oven dried flask containing magnesium turnings (0.408 g, 17mmol) and tetrahydrofuran (10 ml) was added 3-bromoanisole (3.1 g, 17mmol ) and the reaction mixture was heated at reflux. After 2 h, thereaction mixture was cooled to room temperature and5-amino-1-(4-fluorophenyl)-4-(2-pyridylthiocarboxy)pyrazole (1.5g, 4.8mmol) was added and the stirring was continued for 1 h. The reactionmixture was quenched with water and the product was extracted into ethylacetate. The organic layer was washed with aqueous ammonium chloride andbrine and dried over sodium sulfate. The organics were removed in vacuoand the residue was filtered and washed with hexane to give5-amino-1-(4-fluorophenyl)-4-(3-methoxybenzoyl)pyrazole (1.20 g).

Step 2

To an ice-cooled solution of5-amino-1-(4-fluorophenyl)-4-(3-methoxybenzoyl)-pyrazole (3.0 g, 10.0mmol) in methylene chloride (25 ml) was added boron tribromide (51 ml,51 mmol, 1 M solution in methylene chloride). After 1 h, the reactionmixture was poured into brine and the product was extracted into ethylacetate. The organic layer was dried over sodium sulfate, filtered andconcentrated in vacuo to give5-amino-1-(4-fluorophenyl)-4-[3-hydroxybenzoyl]pyrazole (2.4 g).

Step 3

A mixture of 5-amino-1-(4-fluorophenyl)-4-[3-hydroxybenzoyl]pyrazole(1.0 g, 3.3 mmol), tert-butyl bromoacetate (1.4 g, 7.2 mmol) andpotassium carbonate (1 g, 7.2 mmol) in acetonitrile was heated at 70° C.overnight. The reaction mixture was cooled, diluted with ethyl acetateand filtered. The filtrate was concentrated in vacuo and the residue waspurified by flash chromatography (elution gradient: 10% acetone/hexane)to give5-amino-4-[3-(tert-butoxycarbonylmethyloxy)benzoyl]-1-(4-fluorophenyl)pyrazole(1.2 g) as a solid.

Example 115-Amino-4-[3-carboxymethyloxy)benzoyl]-1-(4-fluorophenyl)-pyrazole (119)

Step 1

A mixture of5-amino-4-[3-(tert-butoxycarbonylmethyloxy)benzoyl]-1-(4-fluorophenyl)pyrazole(1.0 g, 3.3 mmol) and trifluoroacetic acid (15 ml, 194 mmol ) inmethylene chloride (15 ml) was stirred overnight at room temperature.The organics were removed in vacuo and the residue was dissolved intoluene. The solution was concentrated and the residue was trituratedbetween ethyl acetate and hexane to give5-amino-4-[3-(carboxymethyloxy)benzoyl]-1-(4-fluorophenyl)pyrazole (0.8g) as a solid.

Example 125-Amino-1-(4-fluorophenyl)-4-[3-(methylaminocarbonylmethyloxy)-benzoyl]pyrazole(34)

Step 1

To a solution of5-amino-4-[3-(carboxymethyloxy)benzoyl]-1-(4-fluorophenyl)-pyrazole (0.5g, 1.43 mmol) in tetrahydrofuran (10 ml) was added carbonyl diimidazole(0.3 g, 1.85 mmol) and the reaction mixture was heated at 60° C. After 1h, methylamine (10 ml, 5 mmol, 0.5 M solution in tetrahydrofuran) wasadded and reaction was continued at 60° C. overnight. The reactionmixture was cooled and diluted with ethyl acetate. The organic layer wasseparated and washed with brine and dried over sodium sulfate. Theorganics were removed in vacuo and the residue was purified by flashchromatography (elution gradient: 20-30% acetone/hexane) to give5-amino-1-(4-fluorophenyl)-4-[3-(methylaminocarbonylmethyloxy)benzoyl]pyrazole(0.25 g, mpt. 195.6-196.3° C.) as a solid.

Proceeding as described in Example 12 above, but substitutingmethylamine with: morpholine gave5-amino-1-(4-fluorophenyl)-4-[3-(morpholin-4-ylcarbonylmethyloxy)-benzoyl]pyrazole(35).

Example 135-Amino-1-(4-fluorophenyl)-4-[3-{3-(morpholin-4-yl)propylamino}benzoyl]-pyrazole(48)

Step 1

Benzoylacetonitrile (14.5 g, 10 mmol) was added to cold fuming nitricacid (50 ml) portionwise over 10 min. The reaction mixture was stirredfor 15 min., and then poured into ice. The solid was filtered off andrecrystallised from ethanol to give 2-(3-nitrobenzoyl)-acetonitrile (5.4g) as a brown solid.

Step 2

A mixture of 2-(3-nitrobenzoyl)acetonitrile (13.75 g, 72.3 mmol) andN,N-diphenylformamidine (14.2 g, 72.3 mmol) in xylene (200 ml) washeated at reflux under nitrogen atmosphere. After 3 h, the reactionmixture was cooled to room temperature and diluted with xylenes to give2-(3-nitrobenzoyl)-3-phenylaminoacrylonitrile (15.7 g) as a yellowsolid.

Step 3

A mixture of 4-fluorophenylhydrazine (2.24 g, 15.57 mmol) and2-(3-nitrobenzoyl)-3-phenylaminoacrylonitrile (4.15 g, 14.16 mmol) inethanol (50 ml) was heated at reflux under nitrogen atmosphere. After 1h, the reaction mixture was cooled to room temperature and stirred foran additional 3 h. The solid was filtered and dried to give5-amino-1-(4-fluorophenyl)-4-(3-nitrobenzoyl)pyrazole (4.5 g) as asolid.

Step 4

A mixture of 5-amino-1-(4-fluorophenyl)-4-(3-nitrobenzoyl)pyrazole (4.0g, 24.52), Fe powder (3.84 g, 68 mmol) and ammonium chloride (3.84,71.78 mmol) in ethanol (135 ml) and water (64 ml) was heated at refluxunder nitrogen atmosphere. After 1 h, the reaction mixture was cooled toroom temperature and stirred overnight. The reaction mixture wasfiltered through Celite® and the filtrate was concentrated in vacuo. Theresidue was partitioned between water and ethyl acetate. The organiclayer was separated and washed with brine, dried over sodium sulfate andconcentrated in vacuo to give5-amino-4-(3-aminobenzoyl)-1-(4-fluorophenyl)pyrazole (3.5 g) as asolid.

Step 5

5-amino-4-(3-aminobenzoyl)-1-(4-fluorophenyl)pyrazole (0.5 g, 1.6 mmol),1-bromo-3-chloropropane (0.26 g, 1.6 mmol) and cesium carbonate (0.52 g,1.6 mmol) in dimethylformamide (25 ml) was heated at 80° C. After 2days, the reaction mixture was cooled to room temperature and dilutedwith ethyl acetate. The organic layer was washed with brine, dried oversodium sulfate and concentrated in vacuo. The residue was purified byflash chromatography (elution gradient: 20% acetone/hexanes) to give5-amino-4-[3-(3-chloropropylamino)benzoyl]-1-(4-fluorophenyl)pyrazole(0.2 g) as a solid.

Step 6

A mixture of5-amino-4-[3-(3-chloropropylamino)benzoyl]-1-(4-fluorophenyl)-pyrazole(0.05 g, 0.13 mmol), morpholine (0.1 ml, 1.1 mmol), potassium carbonate(0.1 g) and potassium iodide (0.1 g) in acetonitrile (3 ml) was heatedat reflux. After 2 days, the reaction mixture was poured into brine andthe product was extracted into ethyl acetate. The organic layer wasseparated, washed with brine, dried over sodium sulfate and concentratedin vacuo. The residue was purified by flash chromatography (elutiongradient: 3% MeOH/CH₂Cl₂) to give5-amino-1-(4-fluorophenyl)-4-[3-{3-(morpholin-4-yl)propylamino}-benzoyl]pyrazoleas a solid.

Example 145-Amino-1-(4-fluorophenyl)-4-[3-{2-(piperidin-1-yl)ethoxy}benzoyl]pyrazoleHCl Salt (81)

Step 1

5-Amino-1-(4-fluorophenyl)-4-[3-hydroxybenzoyl]pyrazole, from Example10, step 2, 1.5 g, 5.05 mmol) was combined with toluene (50 mL).2-bromoethanol (1.79 mL, 25.23 mmol) was added and then the reactionmixture was cooled to 0° C. Triphenylphosphine (5.425 g, 20.69 mmol) anddiethyl azodicarboxylate (3.26 mL, 20.69 mmol) were then added. Thereaction was allowed to warm to room temperature. After stirring for 16hours, the reaction was quenched with a saturated aqueous solution ofNH₄Cl, extracted with ethyl acetate, dried (MgSO₄), filtered, andconcentrated under vacuum. The product(5-amino-1-(4-fluorophenyl)-4-[3(2-bromoethoxy)benzoyl]pyrazole) waspurified by column chromatography on silica gel using 40:1 CH₂Cl₂/MeOHthen stirred with ether for 20 minutes, filtered and dried to give 0.785g of product.

Step 2

5-amino-1-(4-fluorophenyl)-4-[3-(2-bromoethoxy)benzoyl]pyrazole (0.6 g,1.48 mmol) was combined with piperidine (1.47 mL, 14.8 mmol) and ethanol(10 ML) and heated at reflux for 16 hrs. The reaction mixture wasconcentrated under vacuum. The resulting residue was partitioned betweena saturated aqueous solution of NaHCO₃ and ethyl acetate and extractedthree times with ethyl acetate. The organic extracts were dried (MgSO₄),filtered, concentrated under vacuum and purified by columnchromatography on silica gel using 16:1 CH₂Cl₂/MeOH. Dissolving theproduct in ethyl acetate then adding hydrochloric acid (1.0M, 1.0equivalent) formed the hydrochloric salt which was filtered and dried togive 0.413 g of5-amino-1-(4-fluorophenyl)-4-[3-{2-(piperidin-1-yl)ethoxy}benzoyl]pyrazole.HCl(mpt 210.2-211.2° C.).

Proceeding as in Step 2 but replacing piperidine with diethanolamine,dimethylamine, N-methylpiperazine, 2-aminoethanol,bis(2-methoxyethyl)amine, diethylamine, methylamine, ammonia, and3-oxopyridazine the following compounds were obtained.

Mole Structure CPD # HRMS MW Melting Point

121 368.41 184.5-190  

 39 464.922 160.3-160.8

122 494.95 238.0-258.0

123 425.4 217.1-218.0

124 506.49 86.5-93.5

125 440.13 137.8-139.8

126 396.25 204.9-210.3

127 376.817 231.5-232.5

128 419.414 174.5-178.0

Example 155-Amino-1-(4-fluorophenyl)-4-[3-(pyridin-2-ylmethoxy)benzoyl]pyrazole(82)

5-Amino-1-(4-fluorophenyl)-4-[3-hydroxybenzoyl]pyrazole, from Example10, step 2, (0.5 g, 1.68 mmol), 2-pyridylcarbinol (0.81 mL, 8.41 mmol),triphenylphospine (1.81 g, 6.9 mmol), and diethylazodicarboxylate (1.09mL, 6.9 mmol)) were combined in toluene (50 mL). The reaction mixturewas stirred for 16 hours then quenched with a saturated aqueous solutionof NH₄Cl and extracted three times with ethyl acetate. The product wasthen extracted from the ethyl acetate into a 10% aqueous solution ofHCl. The aqueous layer was then neutralized with NaOH and extracted withethyl acetate. The organic extracts were dried (MgSO₄), filtered, andconcentrated under vacuum. The residue was purified by columnchromatography on silica gel using 1:1 hexane/ethyl acetate to give0.165 g of5-amino-1-(4-fluorophenyl)-4-[3-(pyridin-2-ylmethoxy)benzoyl]pyrazole(mpt. 176.1-177.30° C.).

Replacing 2-pyridylcarbinol with glycolic acid,1-(2-hydroxyethyl)-2-pyrrolidinone and 4-hydroxypiperidine gave thefollowing compounds.

Structure CPD # HRMS MWt M. Pt.

119 355.324 215.9-216.2

129 412.03

130 416.882 195.0-220.0

Example 165-Amino-1-(4-fluorophenyl)-4-[3-isopropylaminocarbonyloxybenzoyl]pyrazole(83)

5-Amino-1-(4-fluorophenyl)-4-[3-hydroxybenzoyl]pyrazole, from Example10, step 2, (0.30 g, 1.01 mmol) was combined with K₂CO₃ (0.418 g, 3.03mmol) and THF (6 mL). The mixture was cooled then isopropyl isocyanate(0.12 mL, 1.21 mmol) was warm to room temperature and stirred for 16hours. The reaction mixture was quenched with water, extracted intoethyl acetate, dried (MgSO₄), filtered, and concentrated to dryness. Theresidue was stirred in methanol and dichloromethane for one hour thenfiltered to give 0.118 g of5-amino-1-(4-fluorophenyl)-4-[3-isopropylaminocarbonyloxybenzoyl]pyrazole(mpt. 225.2-230.1° C.).

Replacing isopropyl isocyanate with ethyl isocyanate was made5-amino-1-(4-fluorophenyl)-4-[3-ethylaminocarbonyloxybenzoyl]pyrazole(84). Mpt. 201.2-202.8° C.

Example 17 5-Amino-1-(4-fluorophenyl)-4-[3-iodo benzoyl]pyrazole

Step 1

n-Butyllithium (30.5 ml, 76 mmol, 2.5 M solution in hexane) was addeddropwise to a cooled (0° C.) solution of diisopropylamine (10.6 ml, 76mmol) in 10 ml dry tetrahydrofuran. Once addition was complete, thesolution was kept at 0° C. for 10 minutes and was then cooled to −50° C.This cold LDA solution was then added to a −50° C. solution ofacetonitrile (2.37 ml, 45.3 mmol) and ethyl 4-iodobenzoate (10.0 g, 36.2mmol) in dry tetrahydrofuran (18 ml). Once addition was complete, thereaction was stirred at −50° C. for 3 hours and was subsequently warmedto 0° C. Saturated ammonium chloride was added (20 ml) and the reactionmixture was allowed to warm to room temperature. The product wasextracted into ether and washed with 1N hydrochloric acid (50 ml). Theorganics were washed with brine (50 ml), dried over MgSO₄ and thenconcentrated in vacuo to a red oil. The oil was purified through a smallplug of silica gel using 3:1-2:1 hexanes/ethyl acetate as eluent.Concentration of the column fractions in vacuo gave2-(3-iodobenzoyl)-acetonitrile (8.3 g) as a yellow oil.

Step 2

A mixture of 2-(3-iodobenzoyl)acetonitrile (36.2 g, 133.5 mmol) andN,N-diphenylformamidine (26.2 g, 133.5 mmol) in toluene (200 ml) washeated at reflux under a nitrogen atmosphere. After 8 h, the reactionmixture was cooled to room temperature and diluted with ether (200 ml)to give 2-(3-iodobenzoyl)-3-phenylaminoacrylonitrile (31.2 g) as asolid.

Step 3

A mixture of 4-fluorophenylhydrazine (26.6 g, 211 mmol) and2-(3-iodobenzoyl)-3-phenylaminoacrylonitrile (79 g, 211 mmol) in ethanol(400 ml) was heated at reflux under a nitrogen atmosphere. After 30minutes, the reaction mixture was cooled to room temperature, dilutedwith hexane to give 5-amino-4-(3-iodobenzoyl)-1-(4-fluorophenyl)pyrazole(75.1 g) as a solid.

Replacing 4-fluorophenylhydrazine with 4-methylphenyllhydrazine,3-methoxyphenylhydrazine, 4-sulfamoylphenylhydrazine,2,4-dimethylphenylhydrazine, 2-methylphenylhydrazine,4-chloro-2-methylphenylhydrazine, 4-methylsulfonylphenylhydrazine,2-ethylphenylhydrazine, and 2,4-difluorophenylhydrazine in Step 3 abovegave respectively:

5-amino-4-(3-iodobenzoyl)-1-(4-methylphenyl)pyrazole,

5-amino-4-(3-iodobenzoyl)-1-(3-methoxyphenyl)pyrazole,

5-amino-4-(3-iodobenzoyl)-1-(4-sulfamoylphenyl)pyrazole,

5-amino-4-(3-iodobenzoyl)-1-(2,4-dimethylphenyl)pyrazole,

5-amino-4-(3-iodobenzoyl)-1-(2-methylphenyl)pyrazole,

5-amino-4-(3-iodobenzoyl)-1-(4-chloro-2-methylphenyl)pyrazole,

5-amino-4-(3-iodobenzoyl)-1-(4-methylsulfonylphenyl)pyrazole,

5-amino-4-(3-iodobenzoyl)-1-(2-ethylphenyl)pyrazol, and

5-amino-4-(3-iodobenzoyl)-1-(2,4-difluorophenyl)pyrazole.

Example 18 5-amino-1-(4-fluorophenyl)-4-[3-(1,2-dihydroxyethyl)benzoyl]Pyrazole (85)

Step 1

To a solution of 5-amino-1-(4-fluorophenyl)-4-[3-iodobenzoyl]pyrazole(10 g, 24.6 mmol) in 100 ml dimethylformamide was added vinyltributytin(8.57 g, 27.0 mmol) and tetrakistriphenylphosphine palladium (0) (1.42g, 1.23 mmol). The resulting solution was degassed with argon andsubsequently warmed to 100° C. for 12 hours.

The reaction was cooled to room temperature and was poured into 500 mldistilled water and was extracted 3×100 ml 1:1 ether/ethyl acetate. Theorganics were washed with brine (150 ml), dried over MgSO₄ and thenconcentrated in vacuo to a brown oil. The oil was purified by flashcolumn chromatography using 5:1-4:1 hexanes/ethyl acetate to removenimpurities and 3:1-2:1 hexanes/ethyl acetate to elute the desiredproduct. Concentration of the column fractions in vacuo gave5-amino-1(4-fluorophenyl)-4-[3-vinylbenzoyl] pyrazole (4.48 g) as awhite solid.

Step 2

To a suspension of 5-amino-1(4-fluorophenyl)-4-[3-vinylbenzoyl] pyrazole(4.48 g, 13.95 mmol) in 50 ml t-butanol was added N-methylmorpholineN-oxide (1.79 g, 15.35 mmol) in 50 ml distilled water. To this mixtureat room temperature was added a solution of 2.5% osmium tetraoxide int-butanol (5.25 ml, 0.42 mmol). After 5 hours, the homogenous reactionwas diluted with ethyl acetate (25 ml) and the organics were separatedand washed with brine (25 ml), dried over MgSO₄ and then concentrated invacuo to a brown oil. The oil was purified by flash columnchromatography using 1:1 hexanes/ethyl acetate to remove impurities andethyl acetate to elute the desired product. Concentration of the columnfractions in vacuo gave5-amino-1-(4-fluorophenyl)-4-[3-(1,2-dihydroxyethyl)benzoyl]pyrazole(4.48 g) as a white foam. The foam was triturated to a solid fromhexanes (2.36 g).

Replacing 5-amino-1-(4-fluorophenyl)-4-[3-iodobenzoyl]pyrazole in Step 1above with:

5-amino-1-(2,4-difluorophenyl)-4-[3-iodobenzoyl]pyrazole and

5-amino-1-(2-methylphenyl)-4-[3-iodobenzoyl]pyrazole, gave respectively

5-amino-1-(2,4-difluorophenyl)-4-[3-(1,2-dihydroxyethyl)benzoyl]pyrazole (103) and

5-amino-1-(2-methylphenyl)-4-[3-(1,2-dihydroxyethyl)benzoyl] pyrazole(109).

Example 195-Amino-1-(2,4-difluorophenyl)-4-[3-(1-piperidinylmethyl)-benzoyl]pyrazole(86)

Step 1

To a suspension of5-amino-1-(2,4-difluorophenyl)-4-[3-(1,2-dihydroxyethane)benzoyl]pyrazole (10.1 g, 28 mmol) in 100 ml t-butanol was added 100 mldistilled water and sodium periodate (18.06 g, 84 mmol). After 2 hours,the solid precipitate was collected by vacuum filtration and was washedwith 300 ml distilled water and dried in vacuo to give 8.28 g of5-amino-1-(2,4-difluorophenyl)-4-[3-formylbenzoyl] pyrazole as a whitesolid.

Step 2

To a solution of 5-amino-1-(2,4-difluorophenyl)-4-[3-formylbenzoyl]pyrazole (0.3 g, 0.92 mmol), piperidine (0.1 ml, 1.0 mmol), acetic acid(0.05 ml) in 1,2-dichloroethane (5 ml) was added sodiumtriacetoxyborohydride (0.29 g, 1.37 mmol). After stirring at roomtemperature for 12 hours, the reaction was diluted with 10% hydrochloricacid and ethyl acetate (10 ml). The aqueous layer was separated andneutralized to pH 9 with sodium hydroxide and was then extracted withethyl acetate. The combined organics were separated and washed withbrine (25 ml), dried over MgSO₄ and then concentrated in vacuo to abrown oil. The oil was purified by flash column chromatography using 1:1hexanes/ethyl acetate to remove impurities and ethyl acetate to elutethe desired product. Concentration of the column fractions in vacuo gave5-amino-1-(4-fluorophenyl)-4-[3-(1-piperidinylmethyl)-benzoyl] pyrazoleas an oil (0.211 g). The compound was triturated to a solid fromhexanes/ethyl acetate.

Replacing piperidine in Step1 above with:

morpholine,

N-methylpiperazine,

4-hydroxypiperidine,

2-aminopyridine,

3-aminopyridine,

4-methylimidazole,

3-aminopyrazole, and

2-methylimidazole;

the following compounds were obtained

Structure CPD # HRMS MW MPt

131 398.411 127.3-128.5

132 484.376 238.2-238.6

133 412.438 141.5-145.5

134 405.406

135 405.406

136 393.395

137 508.405

138 507.417

Example 205-Amino-1-(3-methylphenyl)-4-[3-{N-oxidopyridin-3-yl)}benzoyl]pyrazole(70)

A mixture of 5-amino-4-(3-iodobenzoyl)-1-(2-methylphenyl)pyrazole, fromExample 17 (0.98 g, 2.4 mmol), pinacol diboron (0.68 g, 2.7 mmol),[1,1′-bis(diphenylphoshino)ferrocene]dichloropalladium (0.2 g,0.24 mmol)and potassium acetate (0.72 g, 7.3 mmol) in DMF (10 ml) was heated at 80degrees, under argon. After 2 h, the reaction mixture was cooled to roomtemperature and 3-bromopyridine N-oxide (0.47 g, 2.7 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.2 g, 0.24mmol) and 2 M sodium carbonate (6.1 ml, 12.2 mmol) was added and heatedto 80 degrees. After 16 h, the reaction mixture was cooled to roomtemperature, poured into brine and the product extracted into ethylacetate. The organic layer was dried over sodium sulfate, filtered andthen the solution was evaporated to dryness. The residue was purified byflash chromatography (gradient elution: ethyl acetate to 20%methanol/ethyl acetate) to give, after recrystallization frommethanol/ethyl acetate/hexane,5-amino-1-(3-methylphenyl)-4-[3-(N-oxidopyridin-3-yl)benzoyl]pyrazole(0.57 g, mpt. 190.5-191.2).

Replacing5-amino-4-(3-iodobenzoyl)-1-(2-methylphenyl)pyrazole-3-bromopyridineN-oxide with:

5-amino-4-(3-iodobenzoyl)-1-(4-methylphenyl)pyrazole/3-bromopyridine,

5-amino-4-(3-iodobenzoyl)-1-(3-methoxyphenyl)pyrazole/3-bromopyridine,

5-amino-4-(3-iodobenzoyl)-1-(4-sulfamoylphenyl)pyrazole/3-bromopyridine,

5-amino-4-(3-iodobenzoyl)-1-(2,4-dimethylphenyl)pyrazole/3-bromopyridine,

5-amino-4-(3-iodobenzoyl)-1-(2-methylphenyl)pyrazole/3-bromopridine-N-oxide,

5-amino-4-(3-iodobenzoyl)-1-(4-chloro-2-methylphenyl)pyrazole/3-bromopyridine,

5-amino-4-(3-iodobenzoyl)-1-(4-methylsulfonylphenyl)pyrazole/3-bromopyridine,

5-amino-4-(3-iodobenzoyl)-1-(2-ethylphenyl)pyrazole/3-bromopyridine, and

5-amino-4-(3-iodobenzoyl)-1-(2,4-difluorophenyl)pyrazole/2-bromoimidazole,gave respectively the following compounds (as their hydrochloride saltsas appropriate):

5-amino-1-(4-methylphenyl)-4-[3-(pyridin-3-yl)benzoyl]pyrazole (65),

5-amino-1-(3-methoxyphenyl)-4-[3-(pyridin-3-yl)benzoyl]pyrazole (66),

5-amino-1-(4-sulfamoylphenyl)-4-[3-(pyridin-3-yl)benzoyl]pyrazole (68),

5-amino-1-(2,4-dimethylphenyl)-4-[3-(pyridin-3-yl)benzoyl]pyrazole (69),

5-amino-1-(2-methylphenyl)-4-[3-(N-oxidopyridin-3-yl)benzoyl]pyrazole(70),

5-amino-1-(4-chloro-2-methylphenyl)-4-[3-(pyridin-3-yl)benzoyl]pyrazole(73),

5-amino-1-(4-methylsulfonylphenyl)-4-[3-(pyridin-3-yl)benzoyl]pyrazole(75),

5-amino-1-(2-ethylphenyl)-4-[3-(pyridin-3-yl)benzoyl]pyrazole (76), and

5-amino-1-(2,4-difluorophenyl)-4-[3-(imidazol-2-yl)benzoyl]pyrazole(77).

Example 215-Amino-1-(2,4-difluorophenyl)-4-[N-oxidopyridin-3-yl)benzoyl]pyrazole(60)

To a solution of5-amino-1-(2,4-difluorophenyl)-4-[3-(pyridin-3-yl)benzoyl]pyrazole (4.6g, 12.2 mmol) in dichloromethane (100 ml) was added3-chloroperoxybenzoic acid (5.6 g, 18.3 mmol) and the mixture wasstirred at room temperature. After 4 h, a solution of 10% aqueous sodiumsulfite (50 ml) was added. After 0.5 h, the organic layer was separted,washed with brine, dried over sodium sulfate and filtered. The filtratewas concentrated to dryness and the residue purified by flashchromatography (gradient elution: ethyl acetate to 30 % methanol/ethylacetate)to give, after recrystalliztion from methanol,5-amino-1-(2,4-difluorphenyl)-4-[3-(N-oxidopyridin-3-yl)benzoyl]pyrazole (1.3 g, Mpt. 251.1-251.7° C.).

Example 225-Amino-1-(2,4-difluorophenyl)-4-[pyridin-4-yl)benzoyl]pyrazole (61)

A mixture of 5-amino-4-(3-bromobenzoyl)-1-(2.4-difluorophenyl)pyrazole(0.93 g, 2.5 mmol), 4-tributylstannylpyridine (1.0 g, 2.7 mmol) andbis(triphenylphosphine)palladium chloride (0.17 g, 2.5 mmol) in DMF (15ml) was heated at 100 degrees under argon. After 16 h, the reactionmixture was cooled to room temperature and a solution of 10% aqueouspotassium flouride (30 ml) was added. After 1 h, the reaction mixturewas poured into brine, extracted with ethyl acetate, dried over sodiumsulfate, filtered and concentrated to dryness. The residue was purifiedby flash chromatography (gradient elution: 50-100% ethyl acetateihexaneto 5% methanol/ethyl acetate to give, after recrystallizaion frommethanol/ethyl acetate,5-amino-1-(2,4-difluorophenyl)-4-[3-(pyridin-4-yl)benzoyl]pyrazole (0.42g, Mpt. 218-226° C.).

Example 235-Amino-1-(2,4-dimethylphenyl)-4-[3-(pyridin-3-yl)benzoylpyrazole HClSalt (69)

Step 1

Into a solution of n-butyl lithium (165 ml, 264 mmol) in butyl ether(250 ml) at −78 degrees under nitrogen was added 3-bromopyridine (25.4ml, 264 mmol). After 1 h, added diethylmethoxyborane (52 ml, 396 mmol).The mixture was allowed to warm to room temperature. After 16 h, addedwater and brine, separated organic layer, dried over sodium sulfate,then concentrated. The resulting slurry was dissolved in isopropanol(500 ml), cooled and the product isolated by filtration givediethyl(3-pyridyl)borane (29.8 g).

Step 2

A mixture of diethyl(3-pyridyl)borane (176.4 g, 1.2 mole),methyl-3-iodobenzoate(262 g, 1 mole), potassium phosphate (318.4 g, 1.5mole) and tetrakistriphenlyphosphine palladium (0) (57.8 g, 0.05 mole)in DMF (1000 ml) was heated at 80 degrees under argon. After 10 h, themixture was diluted with water and extracted with ethyl acetate. Theorganic layer was filtered and washed with water. To the organicfraction was added concentrated HCL (65 ml). The organic layer wasseparated and extracted with aqueous HCl . The combined acid extractionswere treated with ethyl acetate, followed by 50% aqueous sodiumhydroxide (55 ml). The organic layer was separated, washed with waterand saturated sodium bicarbonate solution, then dried over sodiumsulfate. The solution was filtered and concentrated to givemethyl-3-(pyridin-3-yl)benzoate (145.3 g).

Step 3

To a solution of methyl-3-(pyridin-3-yl)benzoate (126.2 g, 0.59 mole) inTHF (600 ml) was added acetonitrile (37 ml, 0.71 mole) and the reactionwas cooled to −40 degrees. A solution of lithium diisopropyl amide (590ml, 1.18 mole) was added dropwise. After 30 minutes, added methanol (25ml) and after another 30 minutes, added water (110 ml). Allowed thereaction mixture to warm to 10 degrees and added ethyl acetate. Thelayers were separated and the aqueous layer was acidified with 1 M HCl.The aqueous layer was extracted with ethyl acetate, diluted with hexaneand washed with brine. The organic phase was concentrated, then combinedwith N,N′-diphenylformanidine (120 g, 0.61 mole) in 800 ml of ethylacetate. The mixture was stirred at room temperature. After 3 days, theproduct was collected by filtration and recrystallized from isopropanol,hexane to give 2-(3-pyridin-3-yl)phenyl-3-phenylacrylonitrile (100 g).

Step 4

A solution of 2-(3-pyridin-3-ylphenyl)-3-phenylacrylonitrile (1.0 g, 3mmol) and 2,4-dimethyphenylhydrazine (0.4 g, 3 mmol) in ethanol (30 ml)was heated at reflux, under nitrogen. After 6 h, the reaction was cooledto room temperature, concentrated to dryness and the residue purified byflash column chromatography (elution gradient:40-100% ethylacetate/hexane to 10% methanol/ethyl acetate). The purified residue wastaken up in ethyl acetate and HCl/ether added to prepare the salt. Afterrecrystallization from methanol/ethyl acetate was isolated5-amino-1-(2,4-dimethylphenyl)-4-[3-(pyridin-3-yl)benzoylpryrazolehydrochloride salt (0.74 g, m.pt. 250.7-251.8).

Proceeding as above in Example 23, but replacing2,4-dimethyphenylhydrazine in step 4 with:

phenylhydrazine,

2-methyl-4-chlorophenylhydrazine,

4-methoxyphenylhydrazine,

4-methylsulfonylphenylhydrazine,

2-ethylphenylhydrazine,

4-isopropylphenylhydrazine,

2-methoxyphenylhydrazine,

3-chloro-4-methylphenylhydrazine,

3-fluorophenylhydrazine, and

3-fluoro-6-methylphenylhydrazine respectively, the following compoundswere obtained.

Mole Structure CPD # HRMS MW

139 376.845

 73 425.317

140 406.871

 75 454.936

 76 404.899

141 418.926

142 406.871

143 425.317

144 394.835

145 408.862

Example 245-Amino-1-(4-fluorophenyl)-4-[3-{2(R),3-dihydroxypropoxy}benzoyl]Pyrazole (106)

Step 1

To a solution of 5-amino-4-(3-hydroxybenzoyl)-1-(4-fluorophenyl)pyrazole(0.5 g, 1.68 mmol) in 5 ml dry dimethylformamide was addedD-α,β-isopropylideneglycerol-γ-tosylate (0.72 g, 2.52 mmol) followed byanhydrous potassium carbonate (0.695 g, 5.04 mmol). The reation waswarmed to 80° C. under argon. After 24 hours, the reaction was cooled toroom temperature and an additional 500 mg ofD-α,β-isopropylideneglycerol-γ-tosylate was added and the reaction waswarmed back to 80° C. under argon. After 8 additional hours, thereaction was cooled to room temperature and diluted with distilled water(50 ml) and the product was extracted into ether. The combined organicswere washed with brine (50 ml), dried over MgSO₄ and then concentratedin vacuo to a yellow oil. The oil was purified by flash columnchromatography on silica gel using 2:1-1:1 hexanes/ethyl acetate aseluent. Concentration of the column fractions in vacuo gave 556 mg ofthe desired acetal.

Step 2

To a solution of the acetal formed above (0.556 g, 1.35 mmol) inmethanol (10 ml) was added distilled water (2 ml) and p-toluenesulfonicacid monohydrate (5 mg). The solution was warmed to 80° C. under anargon atmosphere. After 2 h, the reaction mixture was cooled to roomtemperature concentrated in vacuo to a yellow oil which was redissolvedin ethyl acetate (50 ml) and saturated sodium bicarbonate (50 ml). Theorganic layer was separated, dried over MgSO₄ and then concentrated invacuo to a white solid. Recrystallization from hexanes/ethyl acetategave 196 mg of the desired diol (Mpt. 150.2-153.0° C.).

Example 25 5-Amino-1-(4-fluorophenyl)-4-thenoyl-pyrazole (114)

Proceeding as described in Example 1, step 2, but replacing2-(3-bromobenzoyl)acetonitrile with 2-(2-thenoyl)acetonitrile and thenfollowing step 3 was obtained5-amino-1-(4-fluorophenyl)-4-(2-thenoyl)-pyrazole.

Proceeding as described in Example 1, step 2, but replacing2-(3-bromobenzoyl)acetonitrile with 2-(2-furanoyl)acetonitrile and thenfollowing step 3 was obtained5-amino-1-(4-fluorophenyl)-4-(2-furanoyl)-pyrazole (115).

Proceeding as described in Example 1, step 2, but replacing2-(3-bromobenzoyl)acetonitrile with 2-(2-methyl-3-furanoyl)acetonitrileand substituting 4-fluorophenylhydrazine in step 3 with2,4-difluorophenylhydrazine was obtained5-amino-1-(2,4-difluorophenyl)-4-(2-methylfuran-3-oyl)-pyrazole (116).

Proceeding as described in Example 1, step 2, but replacing2-(3-bromobenzoyl)acetonitrile with 2-(6-quinolinoyl)acetonitrile andsubstituting 4-fluorophenylhydrazine in step 3 with2,4-difluorophenylhydrazine was obtained5-amino-1-(2,4-difluorophenyl)-4-(6-quinolinoyl)-pyrazole.HCl (117)(mpt. 220-259.2).

Example 26

The following are representative pharmaceutical formulations containinga compound of Formula (I).

Tablet Formulation

The following ingredients are mixed intimately and pressed into singlescored tablets.

Quantity per Ingredient tablet, mg compound of this invention 400cornstarch 50 croscarmellose sodium 25 lactose 120 magnesium stearate 5

Capsule Formulation

The following ingredients are mixed intimately and loaded into ahard-shell gelatin capsule.

Quantity per Ingredient capsule, mg compound of this invention 200lactose, spray-dried 148 magnesium stearate 2

Suspension Formulation

The following ingredients are mixed to form a suspension for oraladministration.

Ingredient Amount compound of this invention 1.0 g fumaric acid 0.5 gsodium chloride 2.0 g methyl paraben 0.15 g propyl paraben 0.05 ggranulated sugar 25.5 g sorbitol (70% solution) 12.85 g Veegum K(Vanderbilt Co.) 1.0 g flavoring 0.035 ml colorings 0.5 mg distilledwater q.s. to 100 ml

Injectable Formulation

The following ingredients are mixed to form an injectable formulation.

Ingredient Amount compound of this invention 0.2 g sodium acetate buffersolution, 0.4M 2.0 ml HCl (1N) or NaOH (1N) q.s. to suitable pH water(distilled, sterile) q.s. to 20 ml

All of the above ingredients, except water, are combined and heated to60-70° C. with stirring. A sufficient quantity of water at 60° C. isthen added with vigorous stirring to emulsify the ingredients, and waterthen added q.s. to 100 g.

Suppository Formulation

A suppository of total weight 2.5 g is prepared by mixing the compoundof the invention with Witepsol® H-15 (triglycerides of saturatedvegetable fatty acid; Riches-Nelson, Inc., New York), and has thefollowing composition:

compound of the invention 500 mg Witepsol ® H-15 balance

Example 27 Inhibition Of p-38 (MAP) Kinase . . . In Vitro Assay

The p-38 MAP kinase inhibitory activity of compounds of this inventionin vitro was determined by measuring the transfer of the γ-phosphatefrom γ-³³P-ATP by p-38 kinase to Myelin Basic Protein (MBP), using the aminor modification of the method described in Ahn, N. G.; et al. J.Biol. Chem. Vol. 266(7), 4220-4227, (1991).

The phosphorylated form of the recombinant p38 MAP kinase was expressedwith SEK-1 and MEKK in E. Coli and then purified by affinitychromatography using a Nickel column.

The phosphorylated p38 MAP kinase was diluted in kinase buffer (20 mM3-(N-morpholino)propanesulfonic acid, pH 7.2, 25 mM β-glycerolphosphate, 5 mM ethylene glycol-bis(beta-aminoethylether)-N,N,N′,N′-tetraacetic acid, 1 mM sodium vanadate, 1 mMdithiothreitol, 40 mM magnesium chloride). Test compound dissolved inDMSO or only DMSO (control) was added and the samples were incubated for10 min at 30° C. The kinase reaction was initiated by the addition of asubstrate cocktail containing MBP and γ-³³P-ATP. After incubating for anadditional 20 min at 30° C., the reaction was terminated by adding 0.75%phosphoric acid. The phosphorylated MBP was then separated from theresidual γ-³³P-ATP using a phosphocellulose membrane (Millipore,Bedford, Mass.) and quantitated using a scintillation counter (Packard,Meriden, Conn.).

Compounds of the invention wer active in this assay. The p-38 inhibitoryactivities (expression as IC₅₀, the concentrating causing 50% inhibitionof the p-38 enzyme being assayed) of somecompounds of the invention are:

CPD # IC₅₀, μM CPD # IC₅₀, μM 1 1.81 19 1.45 2 3.29 21 2.18 3 1.78 272.72 4 6.18 33 1.12 6 1.74 38 6.31 9 1.32 43 6.52 14 1.27 50 1.25

Example 28 Inhibition of LPS-Induced TNF-α Production In THP1 Cells . .. In Vitro Assay

The ability of the compounds of this invention to inhibit the TNF-αrelease was determined using a minor modification of the methodsdescribed in described in Blifeld, C. et al. Transplantation, Vol.51(2), 498-503, (1991).

(a) Induction of TnF biosynthesis:

THP-1 cells were suspended in culture medium [RPMI (Gibco-BRL,Gailthersburg, Md.) containing 15% fetal bovine serum, 0.02 mM2-mercaptoethanol], at a concentration of 2.5×10⁶ cells/ml and thenplated in 96 well plate (0.2 ml aliquots in each well). Test compoundswere dissolved in DMSO and then diluted with the culture medium suchthat the final DMSO concentration was 5%. 20 μl aliquots of testsolution or only medium with DMSO (control) were added to each well. Thecells were incubated for 30 min., at 37° C. LPS (Sigma, St. Louis, Mo.)was added to the wells at a final concentration of 0.5 μg/ml, and cellswere incubated for an additional 2 h. At the end of the incubationperiod, culture supermatants were collected and the amount of TNF-αpresent was determined using an ELISA assay as described below.

(b) ELISA Assay:

The amount of human TNF-α present was determined by a specific trappingELISA assay using two anti-TNF-α antibodies (2TNF-H22 and 2TNF-H34)described in Reimund, J. M., et al. GUT. Vol. 39(5), 684-689 (1996).

Polystyrene 96-well plates were coated with 50 μl per well of antibody2TNF-H22 in PBS (10 μg/ml) and incubated in a humidified chamber at 4°C. overnight. The plates were washed with PBS and then blocked with 5%nonfat-dry milk in PBS for 1 hour at room temperature and washed with0.1% BSA (bovine serum albumin) in PBS.

TNF standards were prepared from a stock solution of human recombinantTNF-α (R&D Systems, Minneapolis, Minn.). The concentration of thestandards in the assay began at

10 ng/ml followed by 6 half log serial dilution's. 25 μl aliquots of theabove culture supernatants or TNF standards or only medium (control)were mixed with 25 μl aliquots of biotinylated monoclonal antibody2TNF-H34 (2 μg/ml in PBS containing 0.1% BSA) and then added to eachwell. The samples were incubated for 2 h at room temperature with gentleshaking and then washed 3 times with 0.1% BSA in PBS. 50 μl ofperoxidase-streptavidin (Zymed, S. San Francisco, Calif.) solutioncontaining 0.416 μg/ml of peroxidase-streptavidin and 0.1% BSA in PBSwas added to each well. The samples were incubated for an additional 1 hat room temperature and then washed 4 times with 0.1% BSA in PBS. 50 gof O-phenylenediamine solution (1 μg/ml O-phenylenediamine and 0.03%hydrogen peroxide in 0.2M citrate buffer pH 4.5) was added to each welland the samples were incubated in the dark for 30 min., at roomtemperature. Optical density of the sample and the reference were readat 450 nm and 650 nm, respectively. TNF-α levels were determined from agraph relating the optical density at 450 nm to the concentration used.

The IC₅₀ value was defined as the concentration of the test compoundcorresponding to half-maximal reduction in 450 nm absorbance. Compoundsof the invention were active in this assay. The activity of selectedcompounds is shown below.

CPD # IC₅₀, μM CPD # IC₅₀, μM 1 1.77 21 0.61 2 6.30 27 0.83 4 1.26 330.14 6 1.04 38 0.69 10 1.62 43 0.17 13 0.77 50 0.51 19 0.17

Example 29 Inhibition of LPS-induced TNF-α Production In Rats . . . InVivo Assay

The ability of the compounds of this invention to inhibit the TNF-αrelease, in vivo, was determined usuing a minor modification of themethods described in described in Zanetti, G.; Heumann, D.; et. al.,“Cytokine production after intravenous or peritoneal Gram-negativebacterial challenge in mice,” J. Immunol., 148, 1890, (1992) and Sekut,L., Menius, J. A., et. al., “Evaluation of the significance of elevatedlevels of systemic and localized tumor necrosis factor in differentanimal models of inflammation,” J. Lab. Clin. Med., 124, 813, (1994).

Female Sprauge-Dawley rats weighing 110-140 grams (Charles River,Hollister, Calif.) were acclimated for one week. Groups containing 8mice each were dosed orally either with the test compounds dissolved inan aqueous vehicle containing 0.9% sodium chloride, 0.5% sodiumcarboxymethyl-cellulose, 0.4% polysorbate 80, 0.9% benzyl alcohol (CMCvehicle) or only vehicle (control group). After 30 min., the mice wereinjected intraperitoneally with 50 μg/kg of LPS (Sigma, St. Louis, Mo.).After 1.5 h, the mice were sacrificed by CO₂ inhalation and blood washarvested by cardiocentesis. Blood was clarified by centrifugation at15,600×g for 5 min. were transferred to clean tubes and frozen at −20°C. until analyzed for TNF-α by ELISA assay (Biosource International,Camarillo, Calif.) following the manufacturer's protocol.

The TNF-α inhibitory activity of selected compounds of the invention,i.e., the measure of the TNF-α content in the test group relative to thevehicle treated group (control group) at 30 mg was:

CPD % CPD % # Inhibition # Inhibition 3 96 19 76 8 86 34 75 16 86

Example 30 Adjuvant Arthritis Assay In Rats . . . In Vivo assay

The Anti-inflammatory activity of the compounds of this invention wasdetermined utilizing adjuvant induced arthritis in rats. Briefly, FemaleSprague Dawley rats, weighing 120-155 g (Charles River, Hollister,Calif.) were acclimated in-house for approximately 1 week prior to use.On day 1, the animals were injected intradermally in the 1/4 proximalportion of the tail with 0.1 ml of a mineral oil (Sigma, St. Louis, Mo.)suspension of heat killed and dried Mycobacterium Butyricum (Difco,Bacto., Des., Lot 115979JA/EXP9/99) at a concentration of 1 mg/0.1 ml.

On day 7, the test compounds were administered in CMC vehicle through today 18. On day 18, following the administration of the compound, animalswere weighed. Clinical scores were obtained to evaluate the intensity ofedema in the four paws and tail. A score of 0 to 4 was assigned to eachpaw and 0 to 3 to the tail such that the maximum score was 19.Polyarthritic animals were scored 0 when no inflammatory signs (swellingand redness) were observed in any of the small joints (intraphalangeal,metacarpophalangeal, metatarsophalangeal) or large joints (wrist/carpus,ankle/tarsus). Animals were scored 1 when slight inflammation wasobserved, 2 moderate edema, 3 severe edema, and 4 when very severe edemawas present. The tail was scored 0 when no signs of edema or necrotictissue was observed, 1 when inocula injection sites and immediatesurrounding tissue exhibit slight edema, 2 when approximately ¼ of thetail was either inflamed or exhibiting necrotic tissue, and 3 when over¼ of the tail exhibited severe necroses or edema. Following clinicalscores, the hind paws were transected at the distal tibia, just proximalto the tarsal joint. The left and right hind paws were weighedindividually, and recorded.

The compounds of the present invention exhibit anti-inflammatoryactivity when tested in this assay.

The foregoing invention has been described in some detail by way ofillustration and example, for purposes of clarity and understanding. Itwill be obvious to one of skill in the art that changes andmodifications may be practiced within the scope of the appended claims.Therefore, it is to be understood that the above description is intendedto be illustrative and not restrictive. The scope of the inventionshould, therefore, be determined not with reference to the abovedescription, but should instead be determined with reference to thefollowing appended claims, along with the full scope of equivalents towhich such claims are entitled.

All patents, patent applications and publications cited in thisapplication are hereby incorporated by reference in their entirety forall purposes to the same extent as if each individual patent, patentapplication or publication were so individually denoted.

What is claimed:
 1. A compound selected from the group of compoundsrepresented by Formula (I):

wherein: R¹ is hydrogen or acyl; R² is hydrogen; A and B are aryl; R³ isheteroalkoxy; R⁴ is selected from the group consisting of: (a) hydrogen;(b) halo; (c) alkyl; (d) alkoxy; and (e) hydroxy; R⁵ is selected fromthe group consisting of: (a) hydrogen; (b) halo; (c) alkyl; (d)haloalkyl; (e) thioalkyl; (f) hydroxy; (g) amino; (h) alkylamino; (i)dialkylamino; (j) heteroalkyl; (k) alkylsulfonyl; (l) aminosulfonyl,mono-alkylaminosulfonyl or di alkylaminosulfonyl; (m) heteroalkoxy; and(n) carboxy; R⁶ is selected from the group consisting of: (a) hydrogen;(b) halo; (c) alkyl; and (d) alkoxy; or a prodrug, an individual isomer,a mixture of isomers or a pharmaceutically acceptable salt thereof. 2.The compound of claim 1, wherein R¹ and R² are hydrogen; and B isphenyl.
 3. The compound of claim 2 wherein A is phenyl.
 4. The compoundof claim 3 wherein R⁴ is hydrogen; and R⁵ is halo or alkyl.
 5. Thecompound of claim 4 wherein R⁵ is chloro, fluoro or methyl; and R⁶ ishydrogen, chloro, fluoro, methyl or methoxy.
 6. The compound of claim 4,wherein R³ is at the 3-position.
 7. The compound of claim 6, wherein R⁵is 4-F and R⁶ is hydrogen.
 8. The compound of claim 4, wherein R⁵ is 2-Fand R⁶ is 4-F.
 9. The compound of claim 4, wherein R⁵ is 4-F and R⁶ ishydrogen.
 10. The compound of claim 4, wherein R⁵ is 2-Me and R⁶ ishydrogen.
 11. The compound of claim 6, wherein R³ is selected from thegroup consisting of 3-dimethylaminopropoxy, 2-dimethylaminoethoxy,2-hydroxyethoxy, and 2,3-dihydroxypropoxy.
 12. The compound of claim 11wherein R⁵ is 4-F or 2-Me and R⁶ is hydrogen.
 13. The compound of claim1, wherein R³ is 2-hydroxyethoxy, 3-hydroxypropoxy,2,3,-dihydroxypropoxy, 2-(1,3-dihydroxy)propoxy or 2-aminoethoxy. 14.The compound of claim 1, wherein R³ is 2-dimethylaminoethoxy,3-dimethylaminopropoxy, (morpholin-4-yl)propoxy or(morpholin-4-yl)ethoxy.
 15. The compound of claim 1, wherein R³ is3-(piperidin-1-yl)propoxy, 2-(piperidin-1-yl)ethoxy,3-(4-methylpiperazin-1-yl)propoxy,3-(2-hydroxymethylpyrrolidin-1-yl)propoxy,3-(2-aminocarbonylpyrrolidin-1-yl)propoxy, 3-diethylaminopropoxy,methylcarbonylnethyloxy, 3-(4-(RS)-hydroxypiperidin-1-yl)propoxy,piperidin-2-methoxy, 2(R),3-dihydroxypropoxy, 2(S),3-dihydroxypropoxy,oxiranylmethoxy, 2(R),3-dihydroxy-3,3-dimethylpropoxy,2(R),3()-dihydroxy-3-methylpropoxy, 2(R),3(S)-dihydroxy-3-methylpropoxy,2(S),3(S)-dihydroxy-3-methylpropoxy,2(S),3(R)-dihydroxy-3-methylpropoxy,2(R),3-dihydroxy-3,3-dimethylpropoxy,2(S),3-dihydroxy-3,3-dimethylpropoxy or 2-(1,3-dihydroxy)propoxy.
 16. Acompound5-amino-1-(4-fluorophenyl)-4-[3-{2,3-dihydroxypropoxy}benzoyl]pyrazole.17. The compound of claim 11, wherein said compound is selected from thegroup consisting of5-amino-1-(4-fluorophenyl)-4-[3-{2(R),3-dihydroxypropoxy}benzoyl]pyrazole,5-amino-1-(4-fluorophenyl)-4-[3-{2(S),3-dihydroxypropoxy}benzoyl]pyrazole,and enantiomerically enriched mixtures thereof.
 18. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof claim 1 and a pharmaceutically acceptable excipient.
 19. A method oftreatment of a disease in a mammal treatable by administration of a p38MAP kinase inhibitor, comprising administration to the mammal atherapeutically effective amount of a compound of claim
 1. 20. Themethod of claim 19 wherein the disease is an inflammatory disease. 21.The method of claim 20 wherein the disease is arthritis.
 22. A processfor preparing a compound of Formula (I) selected from compounds of claim1, which process comprises: (i) reacting a2-keto-3-phenylaminoacrylonitrile of Formula 1:

 with a hydrazine of Formula 2:

where R³, R⁴ R⁵ and R⁶ are as defined in claim 1 to provide a compoundof Formula (I) where R¹ is hydrogen; or (ii) reacting a2-keto-3-phenylaminoacrylonitrile of formula 3:

where Z is either hydroxy, nitro or halo group and R⁴ are as defined inclaim 1 with a hydrazine of formula 2 to provide a compound of formula4:

 followed by conversion of the Z group to the desired R³ group toprovide a compound of Formula (I) where R¹ is hydrogen; (iii) optionallymodifying any of the R¹, R³, R⁴, R⁵ or R⁶ groups; (iv) optionallyconverting the compound of Formula (I) prepared in Steps (i), (ii) or(iii) above, to the corresponding acid addition salt by treatment withan acid; (v) optionally converting the compound of Formula (I) preparedin Steps (i), (ii) or (iii) above, to the corresponding free base bytreatment with a base; and (vi) optionally separating a mixture ofstereoisomers of a compound of Formula (I) prepared in Steps (i)-(v)above, to give a single stereoisomer.
 23. A process for preparing acompound of Formula (I) selected from compounds of claim 1, whichprocess comprises reacting a compound of Formula 5:

where L is a leaving group under organometallic displacement reactionconditions with an organometallic reagent of formula

where M is a metallic moiety to provide a compound of Formula (I) whereR¹ is hydrogen; (ii) optionally modifying any of the R¹, R³, R⁴, R⁵ orR⁶ groups; (iii) optionally converting the compound of Formula (I)prepared in Steps (i) or (ii) above, to the corresponding acid additionsalt by treatment with an acid; (iv) optionally converting the compoundof Formula (I) prepared in Steps (i) or (ii) above, to the correspondingfree base by treatment with a base; and (v) optionally separating amixture of stereoisomers of a compound of Formula (I) prepared in Steps(i) or (iv) above, to give a single stereoisomer.